Neuromodulation catheters with nerve monitoring features for transmitting digital neural signals and associated systems and methods

ABSTRACT

Neuromodulation catheters with nerve monitoring features for transmitting digital neural signals and associated systems and methods are disclosed herein. A neuromodulation catheter configured in accordance with some embodiments of the present technology can include, for example, a handle and an elongated shaft attached to the handle. The shaft can have a proximal portion and a distal portion configured to be moved within a lumen of a blood vessel of a human patient. The neuromodulation catheter can further include an array of contacts at the distal portion of the shaft and a digitizer at the handle or the shaft. The contacts can be configured to detect analog neural signals from within the blood vessel. The digitizer can be configured to receive the analog neural signals from the contacts, digitize the analog neural signals into digital neural signals, and transmit the digital neural signals to a read/write module external to the patient.

TECHNICAL FIELD

The present technology is related to neuromodulation devices. Inparticular, at least some embodiments in accordance with the presenttechnology are related to neuromodulation catheters having nervemonitoring features for transmitting digital neural signals.

BACKGROUND

The sympathetic nervous system (SNS) is a primarily involuntary bodilycontrol system typically associated with stress responses. Fibers of theSNS extend through tissue in almost every organ system of the human bodyand can affect characteristics such as pupil diameter, gut motility, andurinary output. Such regulation can have adaptive utility in maintaininghomeostasis or in preparing the body for rapid response to environmentalfactors. Chronic activation of the SNS, however, is a common maladaptiveresponse that can drive the progression of many disease states.Excessive activation of the renal SNS in particular has been identifiedexperimentally and in humans as a likely contributor to the complexpathophysiology of hypertension, states of volume overload (e.g., heartfailure), and progressive renal disease.

Sympathetic nerves of the kidneys terminate in the renal blood vessels,the juxtaglomerular apparatus, and the renal tubules, among otherstructures. Stimulation of the renal sympathetic nerves can cause, forexample, increased renin release, increased sodium reabsorption, andreduced renal blood flow. These and other neural-regulated components ofrenal function are considerably stimulated in disease statescharacterized by heightened sympathetic tone. For example, reduced renalblood flow and glomerular filtration rate as a result of renalsympathetic efferent stimulation is likely a cornerstone of the loss ofrenal function in cardio-renal syndrome, (i.e., renal dysfunction as aprogressive complication of chronic heart failure). Pharmacologicstrategies to thwart the consequences of renal sympathetic stimulationinclude centrally-acting sympatholytic drugs, beta blockers (e.g., toreduce renin release), angiotensin-converting enzyme inhibitors andreceptor blockers (e.g., to block the action of angiotensin II andaldosterone activation consequent to renin release), and diuretics(e.g., to counter the renal sympathetic mediated sodium and waterretention). These pharmacologic strategies, however, have significantlimitations including limited efficacy, compliance issues, side effects,and others.

BRIEF DESCRIPTION OF THE DRAWINGS

Many aspects of the present technology can be better understood withreference to the following drawings. The components in the drawings arenot necessarily to scale. Instead, emphasis is placed on illustratingclearly the principles of the present technology. For ease of reference,throughout this disclosure identical reference numbers may be used toidentify identical or at least generally similar or analogous componentsor features.

FIG. 1 is a partially schematic illustration of a neuromodulation systemincluding a neuromodulation catheter configured in accordance with anembodiment of the present technology.

FIG. 2 illustrates monitoring and/or modulating renal nerves with theneuromodulation catheter of FIG. 1 in accordance with an embodiment ofthe present technology.

FIG. 3A is an enlarged isometric view of a distal portion of theneuromodulation catheter of FIG. 1 configured in accordance with anembodiment of the present technology.

FIG. 3B is an enlarged partial sectional view of a digitizer at thedistal portion of the neuromodulation catheter of FIG. 3A configured inaccordance with an embodiment of the present technology.

FIG. 3C is an enlarged partial sectional view of a digitizer at thedistal portion of the neuromodulation catheter of FIG. 3A configured inaccordance with another embodiment of the present technology.

FIG. 3D is a side view of the distal portion of the neuromodulationcatheter of FIG. 3A within a blood vessel in accordance with anembodiment of the present technology.

FIGS. 4A-4C are circuit diagrams of amplifier assemblies arranged inquasi-tripole (QT), true-tripole (TT), and adaptive or automatic tripole(AT) configurations, respectively, in accordance with embodiments of thepresent technology.

FIG. 5 is a block diagram illustrating a method of monitoring nerveactivity in accordance with an embodiment of the present technology.

FIG. 6 is an isometric view of a neuromodulation catheter configured inaccordance with another embodiment of the present technology.

FIG. 7 is a side view of a distal portion of a neuromodulation catheterconfigured in accordance with yet another embodiment of the presenttechnology.

FIG. 8 is a side view of a distal portion of a neuromodulation catheterconfigured in accordance with a further embodiment of the presenttechnology.

FIG. 9 is a side view of a distal portion of a neuromodulation catheterconfigured in accordance with yet another embodiment of the presenttechnology.

FIG. 10 is a partial cross-sectional side view of a distal portion of aneuromodulation catheter configured in accordance with a furtherembodiment of the present technology.

FIG. 11 is a side view of a distal portion of a neuromodulation catheterconfigured in accordance with yet another embodiment of the presenttechnology.

FIG. 12 is a conceptual illustration of the sympathetic nervous system(SNS) and how the brain communicates with the body via the SNS.

FIG. 13 is an enlarged anatomic view of nerves innervating a left kidneyto form the renal plexus surrounding the left renal artery.

FIGS. 14A and 14B are anatomic and conceptual views, respectively, of ahuman body depicting neural efferent and afferent communication betweenthe brain and kidneys.

FIGS. 15A and 15B are anatomic views of the arterial vasculature andvenous vasculature, respectively, of a human.

DETAILED DESCRIPTION

Neuromodulation catheters configured in accordance with at least someembodiments of the present technology can include contacts that recordneural signals before and/or after neuromodulation and a digitizer thatdigitizes the recorded neural signals and transmits the digitized neuralsignals to an extracorporeal device. Specific details of severalembodiments of the present technology are described herein withreference to FIGS. 1-15B. Although many of the embodiments are describedwith respect to devices, systems, and methods for intravascular renalneuromodulation, other applications and other embodiments in addition tothose described herein are within the scope of the present technology.For example, at least some embodiments may be useful for intraluminalneuromodulation, for extravascular neuromodulation, for non-renalneuromodulation, and/or for use in therapies other than neuromodulation.It should be noted that other embodiments in addition to those disclosedherein are within the scope of the present technology. Further,embodiments of the present technology can have different configurations,components, and/or procedures than those shown or described herein.Moreover, a person of ordinary skill in the art will understand thatembodiments of the present technology can have configurations,components, and/or procedures in addition to those shown or describedherein and that these and other embodiments can be without several ofthe configurations, components, and/or procedures shown or describedherein without deviating from the present technology.

As used herein, the terms “distal” and “proximal” define a position ordirection with respect to a clinician or a clinician's control device(e.g., a handle of a neuromodulation device). The terms, “distal” and“distally” refer to a position distant from or in a direction away froma clinician or a clinician's control device. The terms “proximal” and“proximally” refer to a position near or in a direction toward aclinician or a clinician's control device. The headings provided hereinare for convenience only and should not be construed as limiting thesubject matter disclosed.

I. SELECTED EXAMPLES OF NEUROMODULATION DEVICES AND RELATED SYSTEMS

FIG. 1 is a partially schematic illustration of a therapeutic system 100(“system 100”) configured in accordance with an embodiment of thepresent technology. The system 100 can include a neuromodulationcatheter 102, a console 104, and a cable 106 extending therebetween. Theneuromodulation catheter 102 can include an elongated shaft 108 having aproximal portion 108 a, a distal portion 108 b, a handle 110 operablyconnected to the shaft 108 at the proximal portion 108 a, and aneuromodulation assembly 120 operably connected to the shaft 108 at thedistal portion 108 b. The shaft 108 and the neuromodulation assembly 120can be 2, 3, 4, 5, 6, or 7 French or one or more other suitable sizes.As shown in FIG. 1, the neuromodulation assembly 120 can include asupport structure 122 carrying an array of two or more contacts 124 anda digitizer 128. The contacts 124 can be configured to detect analogneural signals, and the digitizer 128 can be configured to digitize theanalog neural signals and transmit the digitized neural signals to anextracorporeal device. In certain embodiments, the contacts 124 can beenergy delivery elements, such as electrodes, that not only recordneural signals, but also delivery energy (e.g., RF energy) to a targetsite within a body lumen to provide neuromodulation treatment at thetarget site. In other embodiments, the digitizer 128 itself can includecontacts that measure analog neural signals at the target site, and thecontacts 124 along the support structure 122 can be dedicated to energydelivery. As described in further detail below, in further embodimentsthe contacts 124 can be dedicated to neural recording, and theneuromodulation assembly 120 can include other types of energy deliveryelements that provide neuromodulation treatment using variousmodalities, such cryotherapeutic cooling, ultrasound radiation, etc.

The distal portion 108 b of the shaft 108 can be configured to be movedwithin a lumen of a human patient and locate the neuromodulationassembly 120 at a target site within or otherwise proximate to thelumen. For example, shaft 108 can be configured to position theneuromodulation assembly 120 within a blood vessel, a duct, an airway,or another naturally occurring lumen within the human body. In certainembodiments, intravascular delivery of the neuromodulation assembly 120includes percutaneously inserting a guide wire (not shown) into a bodylumen of a patient and moving the shaft 108 and/or the neuromodulationassembly 120 along the guide wire until the neuromodulation assembly 120reaches a target site (e.g., a renal artery). For example, the distalend of the neuromodulation assembly 120 may define a passageway forengaging the guide wire for delivery of the neuromodulation assembly 120using over-the-wire (OTW) or rapid exchange (RX) techniques. In otherembodiments, the neuromodulation catheter 102 can be a steerable ornon-steerable device configured for use without a guide wire. In stillother embodiments, the neuromodulation catheter 102 can be configuredfor delivery via a guide catheter or sheath (not shown).

Once at the target site, the neuromodulation assembly 120 can beconfigured to detect neural signals by recording electrical activity ofneurons proximate to the target site using the contacts 124 along thesupport member 122 and/or contacts integrated into the digitizer 128.The digitizer 128 can be configured to receive analog neural signalsfrom the contacts 124, digitize the analog neural signals into digitalneural signals, and transmit the digital neural signals to a read/writemodule 130 (shown schematically) and/or other device external to thepatient. The read/write module 130 can be configured to receive andstore the digital neural signals for further use by a clinician oroperator. For example, a clinician can use the neural informationreceived by the read/write module 130 to monitor neural activity before,during, and/or after neuromodulation treatment and/or compile datarelated to neural activity for future use. In the embodiment illustratedin FIG. 1, the read/write module 130 is integrated into the console 104with other features of the system 100. In other embodiments, however,the read/write module 130 can be a separate component and/or part ofanother device (e.g., a computer) communicatively coupled to thedigitizer 128. As explained in further detail below, these digitizedneural signals can be used to make various determinations related to thenerves proximate to the target site, such as whether a neuromodulationtreatment was effective in ablating the nerves at the target site.

The digitizer 128 can communicate with the read/write module 130 viaelectrical wires that run through or along the shaft 108 and the cable106, or via a telemetry module or other type of communication devicethat wirelessly transmits digitized neural signals to a receiver of theread/write module 130. For example, the digitizer 128 can be inductivelycoupled to the read/write module 130. In certain embodiments, thedigitizer 128 can further be configured to filter or otherwise processthe analog signals to differentiate electroneurogram (ENG) signals fromelectromyogram (EMG) signals and/or other background noise in therecorded signal before digitizing the analog signals. The digitizer 128can thus capture, filter, and digitize the analog neural signalsproximate to the site at which they are recorded, rather thantransmitting the recorded analog neural signals through long signalwires that may attenuate or otherwise alter the analog signals.Accordingly, the system 100 is expected to reduce the likelihood ofmeasurement errors or other distortion in the ENG signals.

Before and/or after detecting the neural signals, the neuromodulationassembly 120 can provide or facilitate neuromodulation treatment at thetarget site using the contacts 124 and/or other energy deliveryelements. For example, the contacts 124 can facilitate RF ablation ofnerves proximate to the target site. In other embodiments, theneuromodulation assembly 120 can deliver neuromodulation energy tonerves proximate to the target site using various other modalities, suchas cryotherapeutic cooling, ultrasonic radiation, etc. The digitizer 128can detect neural signals after energy delivery to provide an operatorwith real-time feedback as to the effectiveness of the neuromodulationtreatment.

The console 104 can be configured to control, monitor, supply, and/orotherwise support operation of the neuromodulation catheter 102. Theconsole 104 can further be configured to generate a selected form and/ormagnitude of energy for delivery to tissue at the target site via theneuromodulation assembly 120, and therefore the console 104 may havedifferent configurations depending on the treatment modality of theneuromodulation catheter 102. For example, when the neuromodulationcatheter 102 is configured for electrode-based, heat-element-based, ortransducer-based treatment, the console 104 can include an energygenerator 126 (shown schematically) configured to generate radiofrequency (RF) energy (e.g., monopolar and/or bipolar RF energy), pulsedenergy, microwave energy, optical energy, ultrasound energy (e.g.,intravascularly delivered ultrasound, extracorporeal ultrasound, and/orhigh-intensity focused ultrasound (HIFU)), direct heat energy, radiation(e g, infrared, visible, and/or gamma radiation), and/or anothersuitable type of energy. When the neuromodulation catheter 102 isconfigured for cryotherapeutic treatment, the console 104 can include arefrigerant reservoir (not shown), and can be configured to supply theneuromodulation catheter 102 with refrigerant. Similarly, when theneuromodulation catheter 102 is configured for chemical-based treatment(e.g., drug infusion), the console 104 can include a chemical reservoir(not shown) and can be configured to supply the neuromodulation catheter102 with one or more chemicals.

In selected embodiments, the system 100 may be configured to deliver amonopolar electric field via one or more of the contacts 124. In suchembodiments, a neutral or dispersive electrode 130 (FIG. 2) may beelectrically connected to the generator 126 and attached to the exteriorof the patient. In embodiments including multiple contacts 124, thecontacts 124 may deliver power independently (i.e., may be used in amonopolar fashion), either simultaneously, selectively, or sequentially,and/or may deliver power between any desired combination of the contacts124 (i.e., may be used in a bipolar fashion). In addition, an operatoroptionally may be permitted to choose which contacts 124 are used forpower delivery in order to form highly customized lesion(s) within therenal artery, as desired. One or more sensors (not shown), such as oneor more temperature (e.g., thermocouple, thermistor, etc.), impedance,pressure, optical, flow, chemical, and/or other sensors, may be locatedproximate to, within, or integral with the contacts 124. The sensor(s)and the contacts 124 can be connected to one or more supply wires (notshown) that transmit signals from the sensor(s) and/or convey energy tothe contacts 124.

In various embodiments, the system 100 can further include a controldevice 114 communicatively coupled to the neuromodulation catheter 102.The control device 114 can be configured to initiate, terminate, and/oradjust operation of one or more components (e.g., the contacts 124) ofthe neuromodulation catheter 102 directly and/or via the console 104. Inother embodiments, the control device 114 can be omitted or have othersuitable locations (e.g., within the handle 110, along the cable 106,etc.). The console 104 can be configured to execute an automated controlalgorithm 116 and/or to receive control instructions from an operator.Further, the console 104 can be configured to provide feedback to anoperator before, during, and/or after a treatment procedure via anevaluation/feedback algorithm 118.

FIG. 2 (with additional reference to FIG. 1) illustrates modulatingrenal nerves in accordance with an embodiment of the system 100. Theneuromodulation catheter 102 provides access to the renal plexus RPthrough an intravascular path P, such as a percutaneous access site inthe femoral (illustrated), brachial, radial, or axillary artery to atargeted treatment site within a respective renal artery RA. Bymanipulating the proximal portion 108 a of the shaft 108 from outsidethe intravascular path P, a clinician may advance the shaft 108 throughthe sometimes tortuous intravascular path P and remotely manipulate thedistal portion 108 b (FIG. 1) of the shaft 108. In the embodimentillustrated in FIG. 2, the neuromodulation assembly 120 is deliveredintravascularly to the treatment site using a guide wire 136 in an OTWtechnique. As noted previously, the distal end of the neuromodulationassembly 120 may define a passageway for receiving the guide wire 136for delivery of the neuromodulation catheter 102 using either OTW or RXtechniques. At the treatment site, the guide wire 136 can be at leastpartially withdrawn or removed, and the neuromodulation assembly 120 cantransform or otherwise be moved to a deployed arrangement for recordingneural activity and/or delivering energy at the treatment site. In otherembodiments, the neuromodulation assembly 120 may be delivered to thetreatment site within a guide sheath (not shown) with or without usingthe guide wire 136. When the neuromodulation assembly 120 is at thetarget site, the guide sheath may be at least partially withdrawn orrefracted and the neuromodulation assembly 120 can be transformed intothe deployed arrangement. As described in further detail below, incertain embodiments the digitizer 128 (FIG. 1) can be carried by theguide sheath and communicatively coupled to the contacts 124 (FIG. 1).In still other embodiments, the shaft 108 may be steerable itself suchthat the neuromodulation assembly 120 may be delivered to the treatmentsite without the aid of the guide wire 136 and/or guide sheath.

Image guidance, e.g., computed tomography (CT), fluoroscopy,intravascular ultrasound (IVUS), optical coherence tomography (OCT),intracardiac echocardiography (ICE), or another suitable guidancemodality, or combinations thereof, may be used to aid the clinician'spositioning and manipulation of the neuromodulation assembly 120. Forexample, a fluoroscopy system (e.g., including a flat-panel detector,x-ray, or c-arm) can be rotated to accurately visualize and identify thetarget treatment site. In other embodiments, the treatment site can bedetermined using IVUS, OCT, and/or other suitable image mappingmodalities that can correlate the target treatment site with anidentifiable anatomical structure (e.g., a spinal feature) and/or aradiopaque ruler (e.g., positioned under or on the patient) beforedelivering the neuromodulation assembly 120. Further, in someembodiments, image guidance components (e.g., IVUS, OCT) may beintegrated with the neuromodulation catheter 102 and/or run in parallelwith the neuromodulation catheter 102 to provide image guidance duringpositioning of the neuromodulation assembly 120. For example, imageguidance components (e.g., IVUS or OCT) can be coupled to theneuromodulation assembly 120 to provide three-dimensional images of thevasculature proximate the target site to facilitate positioning ordeploying the multi-electrode assembly within the target renal bloodvessel.

Energy from the contacts 124 (FIG. 1) and/or other energy deliveryelements may then be applied to target tissue to induce one or moredesired neuromodulating effects on localized regions of the renal arteryRA and adjacent regions of the renal plexus RP, which lay intimatelywithin, adjacent to, or in close proximity to the adventitia of therenal artery RA. The purposeful application of the energy may achieveneuromodulation along all or at least a portion of the renal plexus RP.The neuromodulating effects are generally a function of, at least inpart, power, time, contact between the energy delivery elements and thevessel wall, and blood flow through the vessel. The neuromodulatingeffects may include denervation, thermal ablation, and/or non-ablativethermal alteration or damage (e.g., via sustained heating and/orresistive heating). Desired thermal heating effects may include raisingthe temperature of target neural fibers above a desired threshold toachieve non-ablative thermal alteration, or above a higher temperatureto achieve ablative thermal alteration. For example, the targettemperature may be above body temperature (e.g., approximately 37° C.)but less than about 45° C. for non-ablative thermal alteration, or thetarget temperature may be about 45° C. or higher for the ablativethermal alteration. Desired non-thermal neuromodulation effects mayinclude altering the electrical signals transmitted in a nerve.

Hypothermic effects may also provide neuromodulation. For example, acryotherapeutic applicator may be used to cool tissue at a target siteto provide therapeutically-effective direct cell injury (e.g.,necrosis), vascular injury (e.g., starving the cell from nutrients bydamaging supplying blood vessels), and sublethal hypothermia withsubsequent apoptosis. Exposure to cryotherapeutic cooling can causeacute cell death (e.g., immediately after exposure) and/or delayed celldeath (e.g., during tissue thawing and subsequent hyperperfusion).Embodiments of the present technology can include cooling a structure ator near an inner surface of a renal artery wall such that proximate(e.g., adjacent) tissue is effectively cooled to a depth wheresympathetic renal nerves reside. For example, the cooling structure iscooled to the extent that it causes therapeutically effective, cryogenicrenal-nerve modulation. Sufficiently cooling at least a portion of asympathetic renal nerve is expected to slow or potentially blockconduction of neural signals to produce a prolonged or permanentreduction in renal sympathetic activity.

The contacts 124 on the neuromodulation assembly 120 can intravascularlydetect electrical signals before and/or after neuromodulation energy isapplied to the renal artery RA. This information can then be filtered orotherwise processed by the digitizer 128 (FIG. 1) to differentiate theneural activity from other electrical signals (e.g., smooth cell/musclesignals), and the resultant ENG signals can be digitized and transmittedto the read/write module 130 (FIG. 1). In other embodiments, thedigitizer 128 simply digitizes the recorded analog signals and thedigitized signals are processed at an extracorporeal device, such as theread/write module 130 (FIG. 1). Since the digitizer 128 digitizes theanalog neural signals proximate to the site at which they are recorded,the neuromodulation catheter 102 can reduce the likelihood that therecorded analog signals are attenuated or otherwise altered as they maybe while traveling through signal wires. The digitized ENG signals canbe used to determine whether the neuromodulation treatment waseffective. For example, statistically meaningful decreases in the ENGsignal(s) taken after neuromodulation can serve as an indicator that thenerves were sufficiently ablated. Statistically meaningful decreases ordrops in ENG signals generally refers to measureable or noticeabledecreases in the ENG signals.

II. SELECTED EMBODIMENTS OF NERVE MONITORING ASSEMBLIES ANDNEUROMODULATION ASSEMBLIES

FIG. 3A is an enlarged isometric view of the neuromodulation assembly120 of the neuromodulation catheter 102 of FIG. 1 configured inaccordance with an embodiment of the present technology, and FIGS. 3Band 3C are an enlarged partial sectional view of digitizers 128 and 128_(i), respectively, carried by the neuromodulation assembly 120 of FIG.3A. As shown in FIG. 3A, the neuromodulation assembly 120 can include anarray of four contacts 124 (identified individually as first throughfourth contacts 124 a-d, respectively), the digitizer 128, and thesupport member 122 carrying the contacts 124 and the digitizer 128. Inother embodiments the neuromodulation assembly may include a differentnumber of contacts 124 (e.g., 1, 2, 8, 12, etc. contacts 124) and/ormore than one digitizer 128 arranged along the length of the supportmember 122.

The support member 122 can be made from various different types ofmaterials (e.g., metals and/or polymers) suitable for supporting thecontacts 124 and the digitizer 128. In the illustrated embodiment, thesupport member 122 has a helical shape in the deployed state. Thedimensions (e.g., outer diameter and length) of the helical supportmember 122 can be selected to accommodate the vessels or other bodylumens in which the neuromodulation assembly 120 is designed to bedelivered. For example, the axial length of the deployed support member122 may be selected to be no longer than a patient's renal artery (e.g.,typically less than 7 cm), and have a diameter that accommodates theinner diameter of a typical renal artery (e.g., about 2-10 mm). In otherembodiments, the support member 122 can have other dimensions dependingon the body lumen within which it is configured to be deployed. Infurther embodiments, the support member 122 can have other suitableshapes (e.g., semi-circular, curved, straight, etc.), and/or theneuromodulation assembly 120 can include multiple support members 122configured to carry one or more contacts 124 and/or one or moredigitizers 128. The support member 122 may be designed to apply adesired outward radial force to a vessel when expanded to a deployedstate (shown in FIG. 1) to place the contact 124 in contact with theinner surface of the vessel wall. For example, FIG. 3D illustrates thesupport member 122 in a deployed state pressing the contacts 124 againstthe interior wall of a renal artery RA. In embodiments where thedigitizer 128 includes contacts and/or electrodes, the support member122 can be configured to press the digitizer 128 against the wall of therenal artery RA.

As shown in FIG. 3A, the support member 122 can optionally terminatewith an atraumatic (e.g., rounded) tip 138. The atraumatic tip 138 mayreduce the risk of injuring the blood vessel as the helically-shapedsupport member 122 expands and/or as a delivery sheath is refracted fromthe neuromodulation assembly 120. The atraumatic tip 138 can be madefrom a polymer or metal that is fixed to the end of the structuralelement by adhesive, welding, crimping, over-molding, solder, and/orother suitable attachment mechanisms. In other embodiments, theatraumatic tip 138 may be made from the same material as the supportmember 122, and integrally formed therefrom (e.g., by machining ormelting). In further embodiments, the distal end portion of the supportmember 122 may have a different configuration and/or features. Forexample, in some embodiments the tip 138 may comprise a contact, anenergy delivery element, a digitizer, and/or a radiopaque marker.

As discussed above, the contacts 124 can be configured to detect analogelectrical signals at a target site within a body lumen, and thedigitizer 128 can be configured to receive the analog electrical signalsto provide digitized ENG signals to an extracorporeal receiver, such as,the read/write module 130 of FIG. 1. In various embodiments, pairs ofthe contact 124 can be configured to provide multi-polar (e.g., bipolar)recording of electrical activity proximate to a target site in a vessel.The contacts 124 can be arranged in various different pairs to detectelectrical activity from different longitudinal segments and/or otherportions of the vessel. For example, the first contact 124 a can bepaired with any one of the second contact 124 b, the third contact 124c, or the fourth contact 124 d. In other embodiments, other contacts 124can be paired with each other depending on the number of contacts 124 onthe neuromodulation assembly 120 and/or the arrangement of the contacts124 along the support member 122. Multi-polar recording of neuralactivity is expected to reduce noise that would otherwise be collectedvia a single contact because, as described in further detail below,differential amplification of multi-polar recordings provided by thedigitizer 128 can selectively amplify the difference in the signals(e.g., the nerve action potential, i.e., the electrical potentialdeveloped in a nerve cell during cellular activity), while suppressingthe common signals (e.g., the background noise and EMG signals).

In certain embodiments, the neural recordings taken from a first pair ofcontacts 124 can be compared with neural recordings taken from one ormore other pairs of contacts 124. For example, the neural recordingstaken from a first electrode pair consisting of the first and secondcontacts 124 a and 124 b can be compared with the neural recordingstaken from electrode pairs consisting of the first and third contacts124 a and 124 c and/or the first and fourth contacts 124 a and 124 d. Infurther examples, the neural recordings taken from the first and secondcontacts 124 a and 124 b can be compared with those taken from the thirdand fourth contacts 124 c and 124 d, and/or the neural recordings takenfrom the second and third contacts 124 b and 124 c can be compared withthose taken from the third and fourth contacts 124 c and 124 d. Inembodiments including more or less than four contacts 124, neuralrecordings taken from different electrode pairs can be compared witheach other. Comparing the different neural recordings can provide a morecomplete understanding of the neural activity before and/or aftertherapeutic energy delivery, such as whether neuromodulation was moreeffective along a certain longitudinal segment of a vessel. Thecomparison of neural recordings taken from different electrode pairs canalso determine if certain electrode pairs detect stronger, moreconsistent, or otherwise better neural signals than other electrodepairs. In other embodiments, the individual contacts 124 can recordneural activity in a monopolar fashion.

The analog electrical activity recorded by the contacts 124 can betransmitted to the digitizer 128. For example, the contacts 124 can beelectrically coupled to the digitizer 128 via signal wires (not shown;e.g., copper wires) extending from the contacts 124 through or along thesupport member 122 and/or the shaft 108 to the digitizer 128. In otherembodiments, the digitizer 128 can be communicatively coupled tocontacts 124 using other communication means, such as wireless coupling.In the embodiment illustrated in FIG. 3A, the digitizer 128 ispositioned along the support member 122 of the neuromodulation assembly120 proximal to the contacts 124. As further shown in FIG. 3A, adigitizer 128 _(i) (shown in broken lines) can also or alternatively bepositioned distal to the contacts 124 along the support member 122. Inother embodiments, the digitizer 128 can be spaced between the contacts124, or positioned elsewhere along the neuromodulation assembly 120. Infurther embodiments, the neuromodulation assembly 120 can include morethan one digitizer 128. For example, multiple digitizers can bepositioned along the length of the support member 122.

As shown in FIG. 3B, the digitizer 128 can be a small chip (e.g., amicrochip) that is carried by an outer surface of the support member 122or the shaft 108 and covered by a protective encapsulant 134. Thedigitizer chip can have a cross-sectional dimension of about 3×3 mm toabout 5×5 mm, or may have smaller or larger dimensions. In otherembodiments, the digitizer 128 can be positioned within the supportmember 122 or the shaft 108. In further embodiments, the digitizer 128can be positioned on or in other portions of the neuromodulationassembly 120, other portions of the neuromodulation catheter 102 (FIG.1), and/or other portions of the system 100 (FIG. 1). The digitizer 128can be configured to receive the analog neural signals from the contacts124, digitize the analog neural signals into digital neural signals, andtransmit the digital neural signals to an extracorporeal device (e.g.,the read/write module 130 of FIG. 1). For example, the digitizer 128 caninclude an analog to digital circuit that converts the recorded signalsinto digital signals. In various embodiments, the digitizer 128 canfurther be configured to filter the analog signals received from thecontacts 124 to differentiate neural signals (e.g., ENG signals) fromEMG signals and other background noise before digitizing the analogneural signals. For example, the digitizer 128 can include one or moreof the amplifier assemblies described below with reference to FIGS.4A-4C to at least substantially remove EMG and other signals from theanalog neural signals. In other embodiments, the recorded neural signalscan be filtered or otherwise processed after being digitized, such as atan extracorporeal device.

The digitizers 128 can be communicatively coupled to the read/writemodule 130 (FIG. 1) and/or another extracorporeal module by signal wires(not shown) that extend from the digitizer 128 to the read/write module130. For example, when the digitizer 128 is positioned at theneuromodulation assembly 120 and the read/write module 130 isincorporated into the console 104 (FIG. 1), the signal wires can extendthrough or along the shaft 108 and the cable 106 (FIG. 1) to theread/write module 130. In other embodiments, the signal wires can extendalong different lengths of shaft 108 depending upon the location of thedigitizer 128 and the read/write module 130.

In further embodiments, the digitizer 128 can be wirelessly coupled tothe read/write module 130 rather than hardwired thereto. As shown inFIG. 3B, for example, the digitizer 128 can include a telemetry moduleor system 129 that can wirelessly transmit the digitized neural signalsfrom within a human patient to the read/write module 130. Theextracorporeal read/write module 130 can be inductively coupled to thedigitizer 128. In other embodiments, the telemetry module 129 canwirelessly couple the digitizer 128 to the read/write module 130 usingother suitable wireless communication means, such as radio waves,computer systems, etc. In further embodiments, the telemetry module 129and the digitizer 128 can be separate components communicatively coupledto each other.

FIG. 3C illustrates a digitizer 128 _(i) configured in accordance withanother embodiment of the present technology. The digitizer 128 _(i) caninclude several features generally similar to the features of thedigitizer 128 of FIG. 3B. For example, the digitizer 128 _(i) caninclude an analog to digital circuit that converts analog signalsreceived from contacts to digital signals, an amplifier assembly and/orother processing circuit that distinguishes ENG signals from EMG signalsand other background noise, and an optional telemetry module 129 thatwirelessly couples the digitizer 128 _(i) to the read/write module 130(FIG. 1). As shown in FIG. 3C, the digitizer 128 _(i) can furtherinclude a plurality of contacts 124 _(i) (e.g., 2, 3, 4, or moreelectrodes) configured to detect electrical activity proximate to atreatment site within a vessel or other body lumen. The support member122 can be configured to place the contacts 124 _(i) integrated with thedigitizer 128 _(i) into contact with the vessel wall to allow thecontacts 124 _(i) to adequately measure electrical activity.Accordingly, instead of using the contacts 124 (FIG. 3A) to recordneural activity, the digitizer 128 _(i) of FIG. 3C has dedicatedmeasurement contacts 124 _(i) that detect the electrical activity thatis subsequently filtered and digitized. In selected embodiments, thecontacts 124 _(i) of the digitizer 128 _(i) can also be configured todeliver therapeutic and/or non-therapeutic levels of energy to a targetsite. In certain embodiments, the neuromodulation assembly 120 (FIG. 3A)can include more than one digitizer 128 _(i) spaced along the length ofthe support member 122 to record neural activity from various differentportions along a vessel. For example, digitizers 128 _(i) can bepositioned adjacent to each of the contacts 124 along the support member122, or the contacts 124 can be replaced by the digitizers 128. Inembodiments including multiple digitizers 128 _(i) with telemetrymodules 129, the read/write module 130 (FIG. 1) can be multiplexed toreceive digitized neural signals from the various digitizers 128.

As shown in FIG. 3D, in another embodiment a digitizer 128 _(ii) can bepositioned on a distal portion of a guide sheath or guide catheter 135.In this embodiment, the contacts 124 along the support member 122 can beconfigured to record neural activity, and the digitizer 128 _(ii) can becommunicatively coupled to the contacts 124. For example, theneuromodulation assembly 120 can include one or more transmitters (notshown), telemetry modules, and/or other types of communication devicescommunicatively coupled to the contacts 124, and the communicationdevice can wirelessly transmit the recorded analog electrical signalsfrom the contacts 124 to the digitizer 128 _(ii) on the guide catheter135. Similar to the digitizer 128 of FIG. 3B, the digitizer 128 _(ii) onthe guide catheter 135 can filter and digitize analog neural signalsreceived from the contacts 124, and transmit digitized neural signals toan extracorporeal device. For example, the digitizer 128 _(ii) caninclude a telemetry module integrated with or otherwise communicativelycoupled to the digitizer 128 _(ii) to transmit the digitized neuralsignals to the extracorporeal device.

In various embodiments, the contacts 124 can be configured to deliverenergy to nerves proximate to a treatment site in a blood vessel orother body lumen. For example, the contacts 124 can be electrodes thatdeliver therapeutic levels of RF energy and/or other forms of electricalenergy to nerves proximate to the target site. Each electrode can beoperatively coupled to one or more signal wires (not shown; e.g., copperwires) that extend along the body of the shaft 108 to a proximal end ofthe shaft 108 where the signal wires can be operatively connected to anextracorporeal generator (e.g., the generator 126 of FIG. 1) to drivetherapeutic energy delivery. In other embodiments, the telemetry module129 and/or other communication device can wirelessly couple theelectrodes to the generator. The electrodes can be configured to deliverbipolar energy to the nerves and/or deliver energy in a monopolarfashion. As described in further detail below, in other embodiments theneuromodulation assembly 120 can have other suitable energy deliveryelements for delivering various forms of energy to the target site, suchas ultrasound transducers, radiation emitters, cryotherapeuticapplicators, and/or other energy delivery elements.

In operation, the neuromodulation assembly 120 can be intravascularlydelivered to a target site within a blood vessel or other body lumen,and the neuromodulation assembly 120 can be deployed to place thecontacts 124 and, in some embodiments, the digitizer 128, against theinterior wall of the blood vessel. In certain embodiments, one or moreof the contacts 124 along the support member 122 can record electricalactivity from the nerves proximate to the vessel wall, and in otherembodiments contacts 124 _(i) integrated with the digitizer 128 canperform the recording function. The neural activity can be recorded fromthe nerves at their natural state and/or after applying nontherapeuticand/or therapeutic levels of stimulation. The digitizer 128 candistinguish neural signals (e.g., ENG signals) from other signals in therecorded electrical activity and digitize the analog neural signals.This information can be transmitted to the extracorporeal read/writemodule 130 (FIG. 1) wirelessly via the telemetry module 129 or viasignal wires extending through the shaft 108. Because the analog neuralsignals are digitized proximate to where they are recorded, it isexpected that the neural signals received at the read/write module 130are not subject to as much degradation as they would if the analogneural signals had been transmitted through signal wires extending fromthe contacts 124 to the read/write module 130. Accordingly, theneuromodulation assembly 120 with the digitizer 128 positioned on orproximate thereto is expected to reduce the likelihood of measurementerrors, which can be of particular importance when recording smallneural signals that can be on the order of micro volts (μV).

The digitized neural signals can provide a baseline or reference ENGsignal for determining whether subsequent neuromodulation is sufficientto provide a therapeutic effect. In certain embodiments, theneuromodulation assembly 120 can be moved proximally or distally alongthe length of the vessel to record neural signals at a plurality oflocations along the vessel, and the recorded neural signals can beanalyzed using various different decision metrics to determine abaseline ENG signal. For example, the recorded signals can be analyzedby integrating the recorded neural signals, omitting some recordedsignals from consideration (e.g., when the recording appears abnormal orinsufficient for consideration), averaging a plurality of the recordedneural signals (e.g., if they are similar), and/or weighting averages ofthe recorded signals to provide the baseline ENG signal. In oneembodiment, for example, recordings can be taken from a plurality ofelectrode pairs (e.g., the first and second electrodes, the first andthird electrodes, the first and fourth electrodes, the second and thirdelectrodes, etc.), and compared with one another. If any of theelectrode pairs record a signal that differs to a certain degree (e.g.,a threshold percentage) from the signals recorded by the other electrodepairs, the outlier recordings can be discarded and the remainingrecordings can be averaged or otherwise analyzed to determine the ENGsignal. In other embodiments, neural recordings are taken from differentelectrode pairs, and the clearest signal is selected as the baseline ENGsignal.

When the recorded ENG signals alone are insufficient to adequatelymeasure the baseline neural activity, one or more of the contacts 124can be used to stimulate nerves proximate to the treatment site atnon-therapeutic energy levels, and one or more of the other contacts 124can be configured to record the resultant neural activity of themodulated nerves. For example, the generator 126 (FIG. 1) can send astimulating pulse to the first contact 124 a, which in turn appliesnon-therapeutic levels of RF energy or another form of energy to avessel wall sufficient to stimulate the nerves proximate to the vesselwall, and the second and third contacts 124 b and 124 c can record theresultant neural activity (e.g., the action potentials of the nerves)during or after delivery of the energy from the first contact 124 a. Inembodiments in which contacts 124 _(i) are integrated with the digitizer128, the external read/write module 130 (FIG. 1) can communicate withthe digitizer 128 (e.g., via the telemetry modulate 129) to send astimulating pulse to the contacts 124 _(i), and the same contacts 124_(i) and/or contacts 124, 124 _(i) along the support member 122 canrecord the resultant neural activity.

In certain embodiments, the contacts 124 that were used to record nerveactivity can subsequently be used to apply therapeutically-effectivelevels of energy (e.g., RF energy) to the vessel wall to modulate (e.g.,ablate) the nerves proximate to the vessel wall. For example, if therecorded neural activity indicates nerve activity is above a desiredthreshold, the same contacts 124 used to record the neural activity canbe used to ablate the nerves without the operator moving the contacts124. The energy can be delivered from an energy generator (e.g., theenergy generator of FIG. 1) via signal wires extending through the shaft108 and/or via the telemetry module 129. In other embodiments, selectedcontacts 124 or other contacts can be designated solely for recording,and other contacts can be designated for therapeutic energy delivery. Infurther embodiments, the neuromodulation assembly 120 can include otherenergy delivery elements, such as radiation emitters, ultrasoundtransducers, and/or cryotherapeutic applicators, that applytherapeutically-effective levels of energy to the target site.

After applying the neuromodulation energy, one or more of the contacts124, 124 _(i) along the support member 122 and/or integrated into thedigitizer 128 can be used to record analog neural signals from withinthe vessel. The analog neural signals can again be filtered anddigitized by the digitizer 128, and transmitted to the read/write module130 (FIG. 1). As discussed above, ENG signals can optionally be takenfrom recordings at multiple locations within the vessel by moving theneuromodulation assembly 120 along the length of the vessel and/orrecording neural activity from different pairs of contacts 124. Theserecording methods may provide the clinician a better understanding ofthe efficacy of the neuromodulation along the length of the vessel. TheENG signals taken before and after energy application can be compared todetermine the effects of the neuromodulation. For example, decreases inthe ENG signal (compared to the baseline ENG signal) may indicatetherapeutically effective neuromodulation of the target nerves. Thedegree of the decrease may be used as an indicator of the efficacy ofthe neuromodulation. A lack of an ENG signal after neuromodulation maybe indicative of complete denervation of the nerves extending proximateto the vessel. Increases in the ENG signal may indicate that sufficientablation was not achieved, or other factors unrelated to the ablationenergy may cause increases in the ENG signal. If the recorded readingsfrom the nerves indicate that the nerves were not modulated to thedesired extent, the same contacts 124 can be used to reapplytherapeutically-effective levels of energy to the vessel wall tomodulate the nerves proximate to the vessel wall. In certainembodiments, the operator can move the neuromodulation assembly 120longitudinally and/or rotate the neuromodulation assembly 120 to applythe therapeutic energy to nerves along different portions of the vessel.

ENG recordings, which are typically on the order of micro volts (μV),may be obscured by interference from other signals that are typicallygenerated from the muscles nearby (EMG signals on the order of severalmillivolts (mV)). However, as discussed above, the digitizer 128 canfilter or otherwise process the signals recorded at the contacts 124,124 _(i) to at least substantially remove EMG signals or other signalsfrom nearby muscles and/or other background noise that interferes withthe ENG signals. FIGS. 4A-4C, for example, illustrate circuit diagramsof various amplifier assemblies (identified individually as firstthrough third amplifier assemblies 440 a-c, respectively, and referredto collectively as amplifier assemblies 440) for detecting the ENGsignals from the recordings taken at the contacts 124. The contacts 124referred to below and shown in FIGS. 4A-4C can correspond to contactsintegrated with a digitizer (e.g., the digitizer 128 _(i) of FIG. 3C)and/or separate from the digitizer (e.g., the digitizer 128 of FIG. 3B).

Referring to the embodiment illustrated in FIG. 4A, the first amplifierassembly 440 a is arranged in a QT circuit in which two contacts 124(e.g., the first and third contacts 124 a and 124 c) are electricallycoupled to a differential amplifier 442. In other embodiments, adifferent pair of contacts 124 (e.g., the third and fourth contacts 124c and 124 d) can be electrically coupled to the differential amplifier442. The differential amplifier 442 can amplify the difference betweenthe two contacts 124 connected thereto and, in doing so, is expected toat least substantially cancel out (e.g., minimize) EMG signals and otherbackground noise common between the two contacts 124. The extent towhich the QT amplifier assembly 440 a can remove EMG signals depends atleast in part on the contacts 124 being positioned symmetrically withrespect to the vessel and the uniformity of the tissue (e.g., inthickness and consistency) in contact with the contacts 124. Twocontacts (e.g., the second and fourth contacts 124 b and 124 d) can beshorted together to reduce the potential gradient and, therefore, theEMG interference detected by the contacts 124. One of the remainingcontacts 124 (e.g., the second or fourth contact 124 b or 124 d) canserve as a reference or ground electrode. In other embodiments, anotherelectrode 430 attached to the patient (e.g., the dispersive electrode130 of FIG. 2) can serve as the reference electrode.

Referring to FIG. 4B, the second amplifier assembly 440 b is arrangedwith the contacts 124 in a TT circuit. The TT circuit includes threedifferential amplifiers (identified individually as first through thirddifferential amplifiers 442 a-c, respectively, and referred tocollectively as differential amplifiers 442). The first and secondcontacts 124 a and 124 b can be electrically coupled to the firstdifferential amplifier 442 a, and the second and third contacts 124 band 124 c can be electrically coupled to the second differentialamplifier 442 b. The first and second differential amplifiers 442 a and442 b can in turn be coupled to a double-differential amplifier, i.e.,the third differential amplifier 442 c. In this TT amplifier assembly440 b, the contacts 124 are each connected to an input of a differentialamplifier (which has a high impedance load), and therefore the TTamplifier assembly 440 b is insensitive to electrode impedance. Thisreduces phase differences caused by electrode capacitance, and thereforecauses the TT amplifier assembly 440 b to be unaffected by electrodemismatches (e.g., when the electrodes are not positioned symmetrically).

In various embodiments, the gain of first stage amplifiers defined byfirst and second differential amplifiers 442 a and 442 b can bemanipulated to compensate for non-uniform readings from the twoelectrode pairs, such as the first and second contacts 124 a and 124 band the second and third contacts 124 b and 124 c. For example, thefirst stage amplifiers 442 a and 442 b can be varied to compensate fornon-uniform tissue contact between the electrode pairs 124 a-b and 124b-c. A second stage differential amplifier defined by the thirddifferential amplifier 442 c can then be used to at least substantiallycancel out EMG signals (e.g., by matching the equal in amplitude butopposite in phase EMG potential gradient at each half of the circuit).At the same time, the TT amplifier assembly 440 b is expected to producehigher ENG signals (e.g., higher than the QT amplifier assembly 440 a ofFIG. 4A), and improve the ENG to EMG ratio by tuning of the gains (e.g.,using low noise first stage differential amplifiers). In otherembodiments, two different pairs of contacts 124 can be electricallycoupled to the first stage differential amplifiers, and/or additionalcontacts can be coupled in pairs to differential amplifiers that are inturn electrically coupled to a subset of differential amplifiers. Aswith the QT circuit of FIG. 4A, the fourth contact 124 d and/or anotherelectrode can serve as a reference/ground electrode.

In FIG. 4C, the third amplifier assembly 440 c is arranged with thecontacts 124 in an AT circuit. Similar to the TT circuit, the AT circuitincludes two pairs of contacts 124 (e.g., the first and second contacts124 a and 124 b and the second and third contacts 124 b and 124 c)electrically coupled to two corresponding differential amplifiers 442(i.e., the first and second differential amplifiers 442 a and 442 b),which are in turn coupled to the third differential amplifier 442 c. Inaddition, the output of the first stage differential amplifiers (i.e.,the first and second differential amplifiers 442 a and 442 b) are alsoelectrically coupled to controller 444. The controller 444 can allow theAT circuit to automatically compensate for electrode errors using aclosed-loop control approach (i.e., automatic feedback gain adjustment).For example, the controller 444 can include two additional variable gainamplifiers, two rectifiers, a comparator, an integrator, and a feedbackamplifier to provide the desired automatic feedback gain adjustment. TheAT amplifier assembly 440 c applies a frequency independent method, andtherefore is expected to reduce EMG interference and at the same timeretain neural information at the ENG bandwidth of interest. As discussedabove with regard to the QT and TT circuit configurations, the fourthcontact 124 d and/or another electrode can serve as a referenceelectrode, and/or the contacts 124 can be arranged in different pairsthan those shown in FIG. 4C.

Any one of the amplifier assemblies 440 can be incorporated into adigitizer (e.g., the digitizer 128 of FIGS. 1-3D) to differentiate ENGsignals from EMG signals and other background noise, and thereby detectneural activity. The detected ENG signals can be transmitted to anextracorporeal device and displayed on a screen, monitor, or other typeof display in real-time for an operator (e.g., a physician) to viewduring and/or after a procedure. In other embodiments, ENG signals canbe filtered from the EMG signals using analog or digital filteringapplied to the output signal, and the filtered ENG signals can be usedin conjunction with amplifier neutralization. In further embodiments,high-order filtering may be used to separate ENG signals from slower EMGsignals because the frequency spectra of the two signals overlap, butthe peaks of their power spectral densities differs by about an order ofmagnitude. In still further embodiments, algorithms and/or artificialneural networks can be used to separate ENG signals from EMG signals.

FIG. 5 is a block diagram illustrating a method 500 of monitoring nerveactivity using the system 100 of one of the embodiments of FIGS. 1-4C oranother suitable system in accordance with an embodiment of the presenttechnology. The method 500 can include intravascularly placing aneuromodulation assembly (e.g., the neuromodulation assembly 120 ofFIG. 1) at a target site in a blood vessel (block 505), and deployingthe neuromodulation assembly from a delivery state (e.g., a low-profileconfiguration) to a deployed state (e.g., an expanded configuration) toplace two or more contacts (e.g., electrodes) and/or other energydelivery elements at least substantially in contact with the vessel wall(e.g., as shown in FIG. 3D; block 510).

The method 500 can further include recording analog neural signals atthe target site via the contacts (block 515), and digitizing the analogneural signals with a digitizer (e.g., the digitizer 128 of FIGS. 3A-3D)positioned proximate to the contacts (block 520). In certainembodiments, the contacts can be spaced along the neuromodulationassembly and communicatively coupled to the digitizer, and in otherembodiments the contacts can be integrated with the digitizer such thatthe contacts and the digitizer define a single module. The digitizer canbe attached to the neuromodulation catheter at a location such that theamplitude of the recorded analog neural signals remains above a level atwhich the analog neural signals can be accurately digitized from othersignals detected by the contacts. The recorded electrical activity mayinclude EMG signals from the surrounding muscle fibers and/or otherbackground noise. Accordingly, an amplifier assembly can be used tofilter the analog neural signal before the digitizing step. For example,the digitizer can include an amplifier assembly that is electricallycoupled to the contacts in a QT, TT, and/or AT arrangement (e.g., asdescribed above with reference to FIGS. 4A-4C).

The digitized neural signals can then be transmitted to anextracorporeal read/write module (e.g., the read/write module 130 ofFIG. 1) where they can be viewed and/or analyzed by a clinician or acomputer (block 525). In certain embodiments, the digitizer can includea telemetry module that wireless transmits the digitized neural signalsto the read/write module. For example, the digitizer and the read/writemodule can be inductively coupled to each other. In other embodiments,the digitized neural signals can be transmitted to read/write module viawires that extend from the digitizer to the read/write module.

In various embodiments, neural activity can be detected from severallocations at and/or proximate to the target site, and the digitizedneural signals from each location can be transmitted to the read/writemodule. These digitized signals can be transmitted individually, or thedigitizer may include a memory that stores a plurality of digitizedneural signals and sends them together to the read/write module. At theread/write module and/or other device communicatively coupled thereto,the neural signals from the various locations can be averaged to providea baseline ENG of neural activity before neuromodulation. In otherembodiments, neural recordings can be taken from different pairs ofcontacts and compared to provide an understanding of the neural activityalong the vessel and/or to select which contact pair or pairs providethe best ENG signals (e.g., the clearest or strongest ENG signals). Ifthe recorded ENG signals are low or indeterminable, the operator mayoptionally stimulate neural activity with a short current pulse suppliedby one of the contacts (e.g., a first electrode), and the other contacts(e.g., a second, third, and/or fourth electrode) can be used to recordthe resultant neural activity.

After a pre-neuromodulation ENG signal has been detected, the method 500can continue by delivering neuromodulation energy to the target site(block 530). In certain embodiments, the same contacts that are used todetect the neural activity can be used to deliver the neuromodulationenergy to the treatment site. In other embodiments, the neuromodulationassembly can include separate energy delivery elements dedicated toneuromodulation treatment, such as separate electrodes, cryotherapeuticapplicators, ultrasound transducers, and/or radiation emitters.

The method 500 can further include detecting neural signals proximate tothe treatment site after the neuromodulation energy has been applied(block 535). As discussed above, the neural signals can be detected byrecording electrical activity via the contacts, filtering the recordedanalog signals to distinguish the neural signals from other electricalactivity, and digitizing the analog neural signals. The operator canoptionally record neural activity from a plurality of different contactpairs and/or at a plurality of locations proximate to the target site,and the various neural recordings can be compared with each other and/oraveraged.

The digitizer can transmit the digitized neural signals to theextracorporeal read/write module, and the post-neuromodulation ENGsignals can then be compared with the ENG signals taken beforeneuromodulation (block 540). Decreases (e.g., substantial decreases) inthe amplitude and/or other parameter of the ENG signals afterneuromodulation may indicate sufficient treatment of nerves proximate tothe target site. For example, a decrease in amplitude of the ENG signalsof 20%, 30%, 40%, 50%, 60%, 70%, 80%, and/or over 90% may indicatesufficient treatment of the target nerves. Using this information, themethod 500 can then determine whether the nerves have been adequatelymodulated (block 545). For example, if the amplitude observed in ENG isbelow a threshold value, then the neuromodulation step may haveeffectively modulated or stopped conduction of the adjacent nerves andthe neuromodulation process can be considered complete. However, ifnerve activity is detected above a threshold value, the process ofneuromodulating (block 530) and monitoring the resultant nerve activity(block 535) can be repeated until the nerves have been effectivelymodulated. The method 500 can optionally be repeated after a time period(e.g., 5-30 minutes, 2 hours, 1 day, etc.) to confirm that the nerveswere adequately ablated (e.g., rather than merely being stunned).

The method 500 and the system 100 (FIG. 1) used to implement the method500 can monitor neural activity and deliver therapeutic energy tomodulate nerves to provide real-time feedback of the effectiveness of aneuromodulation treatment. By digitizing the neural signals proximate tothe place at which they are recorded (e.g., at the contacts), the method500 can reduce attenuation and/or other distortion that the analogneural signals may incur had they been transmitted elsewhere beforefurther filtering or processing. The method 500 also provides therecording and energy delivery steps in a single device (e.g., theneuromodulation catheter 102 (FIG. 1)). Accordingly, the method 500 canfacilitate more efficient procedure times than if these steps wereperformed by two separate devices that would need to be deliveredindependently of each other to the treatment site. In variousembodiments, the same elements (e.g., electrodes) can be used to provideboth the recording and energy delivery function. In addition, the method500 can differentiate ENG signals from EMG signals using recordingstaken intravascularly positioned contacts.

FIG. 6 is an isometric view of a neuromodulation catheter 602 configuredin accordance with another embodiment of the present technology. Theneuromodulation catheter 602 can include various features generallysimilar to those of the neuromodulation catheter 102 described abovewith reference to FIGS. 1-4C. For example, the neuromodulation catheter602 can include an elongated shaft 608 with a handle 610 at a proximalportion 608 a of the shaft 608 and a neuromodulation assembly 620 at adistal portion 608 b of the shaft 608. The neuromodulation assembly 620can include a plurality of contacts 624 carried by a support member 622that places the contacts 624 against an interior wall of a body lumenwhen the neuromodulation assembly 620 is in a deployed state. In certainembodiments, the contacts 624 can be electrodes that record analogneural signals and/or deliver therapeutic neuromodulation energy tonerves proximate to the target site.

The neuromodulation catheter 602 can further include a digitizer 628that receives the analog signals from the contacts 624, filters theanalog neural signals to provide ENG signals, and digitizes the analogneural signals into digital neural signals. In the embodimentillustrated in FIG. 6, the digitizer 628 is coupled to the handle 610 atthe proximal portion 608 a of the shaft 608. The digitizer 628 cantherefore receive the analog neural signals from the contacts 624 viawires that extend along the length of the shaft 608. In otherembodiments, the contacts 624 can be wirelessly coupled to the digitizer628 via a telemetry module (not shown) operably coupled to the contacts624. Once the neural signals have been received and digitized at thedigitizer 628, the digitizer 628 can transmit the digitized neuralsignals to a separate read/write module (not shown, e.g., the read/writemodule 130 of FIG. 1) where they can be further processed and/or viewedby an operator. The digitized neural signals can be transmitted viasignal wires that extend through a cable 606 attached to the handle 610and/or a separate cable or wire that extends directly from the digitizer628. In other embodiments, the digitizer 628 can include a telemetrymodule (not shown) that can wirelessly transmit the digitized neuralsignals to the read/write module.

As shown in FIG. 6, the digitizer 628 can be stored within a housing 637that is separate from and releasably coupled to the handle 610. Forexample, the housing 637 may include an electrical connector (e.g., aphone connector) that is received by a corresponding port in the handle610. This electrical connection allows the digitizer 628 to receive theanalog signals recorded by the contacts 624 via wires that extendthrough the shaft 608. In other embodiments, the housing 637 can beattached to the exterior of the handle 610 using a temporary adhesiveand/or a mechanical connector, without being hardwired to the contacts624 connected to features of the handle 610. In this embodiment, theanalog neural signals can be wirelessly transferred to the digitizer628. Regardless of the manner in which the digitizer 628 is coupled tothe contacts 624, the detachable housing 637 can be removed from thehandle 610 after use so that the digitizer 628 can be used with otherneuromodulation catheters. In other embodiments, the digitizer 628 maybe integrated into the handle 610 itself. Though spaced further from thecontacts 624 than the digitizers 128, 128 _(i) and 128 _(ii) of FIGS.3A-3D, the digitizer 628 of FIG. 6 can still capture analog neuralsignals closer to the contacts 624 than a read/write module or computerspaced apart from the neuromodulation catheter 620, and thereby reduceerrors that may otherwise be introduced into the neural recordings.

In other embodiments, the neuromodulation catheter 602 can include adigitizer positioned elsewhere on device. For example, FIG. 6illustrates a digitizer 628 _(i) (shown in broken lines) positioned onthe proximal portion 608 a of the shaft 608. The digitizer 628 _(i) canbe attached to an exterior surface of the shaft 608 similar to thedigitizer shown in FIG. 3B, or can be positioned within the shaft 608.Similar to the digitizer 628 carried by the handle 610, the proximallypositioned digitizer 628 _(i) can either be hardwired to the contacts624 via wires that extend through the shaft 608, or may be wirelesslycoupled to the contacts 624. The digitizer 628 _(i) can capture anddigitize the analog signal relatively close to the contacts 624, andthereby at least partially reduce distortion in the ENG signal. Infurther embodiments, the 628 _(i) can be positioned along anotherportion of the shaft 608.

FIG. 7 is a side view of a neuromodulation assembly 720 at a distalportion of a neuromodulation catheter configured in accordance withanother embodiment of the present technology. The neuromodulationassembly 720 includes various features generally similar to those of theneuromodulation assembly 120 described above with reference to FIGS.1-3D. For example, the neuromodulation assembly 720 can be attached to adistal portion 708 b of a shaft 708, and can include a plurality ofcontacts 724 (e.g., electrodes) configured to contact a vessel wall Vwhen the neuromodulation assembly 720 is in a deployed state (e.g.,shown in FIG. 7). In addition, the neuromodulation assembly 720 caninclude a digitizer 728 carried by the distal portion 708 b of the shaft708 proximal to the contacts 724. In other embodiments, the digitizer728 can be positioned elsewhere on the neuromodulation assembly 720.

In the embodiment illustrated in FIG. 7, the contacts 724 are supportedby an expandable mesh structure 750. For example, the contacts 724 maybe proximate to, adjacent to, adhered to, and/or woven into the meshstructure 750. In other embodiments, the contacts 724 may also be formedby the mesh structure 750 itself (e.g., the fibers of the mesh may becapable of delivering energy). Whether the contacts 724 are mounted onor integrated into the mesh structure 750, the mesh structure 750 can beexpanded such that the contacts 724 contact with the vessel wall V. Oncein contact with the vessel wall V, the contacts 724 may deliver powerindependently of each other (i.e., may be used in a monopolar fashion),either simultaneously or progressively, and/or may deliver power betweenany desired combination of the elements (i.e., may be used in a bipolarfashion). In addition, the contacts 724 can perform a nerve monitoringfunction by detecting neural activity before and/or after in energydelivery. In other embodiments, some of the contacts 724 on the meshstructure 750 can be configured solely for nerve recording and the othercontacts can be configured for energy delivery.

At least some of the contacts 724 on the mesh structure 750 can becommunicatively coupled to the digitizer 728 via signal wires or awireless coupling means such that the digitizer 728 can receive theanalog signals recorded by the contacts 724, filter and digitize theanalog signals, and transmit the digitized neural signals to anextracorporeal device via a wired or wireless connection. In otherembodiments, the digitizer 728 can be carried by the mesh structure 750,and can itself include contacts that record analog neural signals whenplaced in contact with the vessel wall V.

As shown FIG. 7, the neuromodulation assembly 720 can further include atube 752 or other type of shaft that extends through the length of themesh structure 750, and a distal member 738 (e.g., a collar, shaft, orcap) at the distal end portion of the mesh structure 750 coupled to thetube 752. The distal member 738 can include a rounded distal portion toprovide atraumatic insertion of the neuromodulation assembly 720 into avessel and an opening 754 that allows the neuromodulation assembly 720to be threaded over a guide wire 756 for intravascular delivery to atarget site. In addition, the shaft 708, the tube 752, the meshstructure 750, and/or the distal member 738 may have a lumen sized andshaped to slideably accommodate a control wire 758. The control wire 758can facilitate the expansion and/or contraction of the mesh structure750 when it is pulled or pushed (e.g., at the proximal end of theneuromodulation catheter). For example, pulling (i.e., an increase intension) of control wire 758 may shorten the mesh structure 750 toincrease its diameter placing it in an expanded configuration (e.g.,FIG. 7), whereas pushing (i.e., an increase in compression) of controlwire 758 may lengthen the mesh structure 750 to a compressedconfiguration. As shown in FIG. 7, the control wire 758 can be a hollowtube that can be passed over the guide wire 756. In other embodiments,the control wire 758 may be a solid structure (e.g., made from a metalor polymer). Further details and characteristics of neuromodulationassemblies with mesh structures are including in International PatentApplication No. PCT/US2011/057153 (International Patent ApplicationPublication No. WO2012/054862), which is herein incorporated byreference in its entirety.

FIG. 8 is a side view of a neuromodulation assembly 820 at a distalportion of a neuromodulation catheter configured in accordance with yetanother embodiment of the present technology. The neuromodulationassembly 820 includes various features generally similar to those of theneuromodulation assemblies 120 and 720 described above. For example, theneuromodulation assembly 820 can be attached to a distal portion 808 bof a shaft 808, and can include a plurality of contacts 824 configuredto be placed into contact with a vessel wall V when the neuromodulationassembly 820 is deployed within a vessel (e.g., FIG. 8). An atraumatic(e.g., rounded) distal member 838 can be attached to the distal portionof the neuromodulation assembly 820 and can include a distal guide wireopening 854 to facilitate intravascular delivery of the neuromodulationassembly 820 to a target site. In addition, the neuromodulation assembly820 can include a digitizer 828 carried by the distal portion 808 b ofthe shaft 808 and communicatively coupled to the contacts 824. In otherembodiments, the digitizer 828 can be positioned elsewhere on theneuromodulation assembly 820.

In the embodiment illustrated in FIG. 8, the neuromodulation assembly820 further includes a plurality of supports 860 that define anexpandable basket structure and carry the contacts 824. The proximalends of the supports 860 can be attached or otherwise connected to thedistal portion 808 b of the shaft 808, and the distal ends of thesupports 860 can be attached or otherwise connected to the distal member838. At least one of the distal portion 808 b of the shaft 808 and thedistal member 838 can be moveable along the longitudinal dimension A-Aof the shaft 808 to transform the neuromodulation assembly 820 from alow-profile delivery state to an expanded deployed state in which thecontacts 824 contact in the inner wall V of at a target site.

As shown in FIG. 8, the contacts 824 can be spaced angularly apart fromeach other around the longitudinal dimension A-A of the shaft 808 at acommon area along the length of the longitudinal dimension A-A. Thisarrangement places the contacts 824 in contact with the vessel wall V toprovide an at least substantially circumferential exposure (e.g., forneural recording and/or neuromodulation) in a common plane perpendicularto the longitudinal dimension A-A of the shaft 808. In otherembodiments, the contacts 824 can have other suitable configurations.For example, one or more contacts 824 can be spaced along the length ofthe supports 860 to provide nerve monitoring and/or neuromodulation atdifferent zones along the length of the vessel and/or theneuromodulation assembly 820 can include a different number of supports860 than the four supports 860 illustrated in FIG. 8 (e.g., to providenerves with more fully circumferential exposure the contacts 824). Infurther embodiments, the contacts 824 can be positioned in a staggeredrelationship relative to each other along the length of theneuromodulation assembly 820. For example, first electrodes 824 a (shownin broken lines) at a proximal portion of two of the supports 860 can belongitudinally offset from second contacts 824 b (shown in broken lines)on distal portions of two other longitudinal supports 860. The firstelectrodes 824 a can also be angularly offset from the second electrodes824 b by, for example, 90° or some other suitable angle.

At least some of the contacts 824 on supports 860 can be communicativelycoupled to the digitizer 828 via signal wires or a wireless couplingmeans such that the digitizer 828 can receive the analog signalsrecorded by the contacts 824, filter and digitize the analog signals,and transmit the digitized neural signals to an extracorporeal devicevia a wired or wireless connection. In other embodiments, the digitizer828 can be carried by one of the supports 860, and can itself includecontacts that record analog neural signals when placed in contact withthe vessel wall V. In further embodiments, the neuromodulation assembly820 can include a plurality of digitizers 828 with contacts integratedtherein, and the digitizers 828 can be spaced along various portions ofthe supports 860 to detect neural signals along various portions of thevessel wall V.

The contacts 824 can be electrodes configured to provide both energydelivery (e.g., RF energy) and recording of electrical activity at thetarget site. In other embodiments, some of the contacts 824 can servesolely as contacts for detecting neural signals while others areconfigured for energy delivery. In further embodiments, at least some ofthe contacts 824 can be configured to provide a form of energy otherthan electrical current (e.g., RF energy) to the target site, whileothers can provide the nerve monitoring function. For example, at leastsome of the contacts 824 can be defined by radiation emitters thatexpose target nerves to radiation at a wavelength that causes apreviously administered photosensitizer to react, such that it damagesor disrupts the nerves. The radiation emitters can be optical elementscoupled to fiber optic cables (e.g., extending through the shaft 808)for delivering radiation from a radiation source (e.g., an energygenerator) at an extracorporeal location to the target tissue at thevessel, or may be internal radiation sources (e.g., LEDs) that areelectrically coupled to a power source at an extracorporeal location viaelectrical leads within the shaft 808.

In embodiments where one or more of the contacts 824 are defined byradiation emitters, a photosensitizer (e.g., oxytetracycline, a suitabletetracycline analog, and/or other suitable photosensitive compounds thatpreferentially bind to neural tissue) can be administered to a patient(e.g., orally, via injection, through an intravascular device, etc.),and preferentially accumulate at selected nerves (e.g., rather thanother tissues proximate to the selected nerves). For example, more ofthe photosensitizer can accumulate in perivascular nerves around a bloodvessel than in the non-neural tissues of the blood vessel. Themechanisms for preferentially accumulating the photosensitizer at thenerves can include faster uptake by the nerves, longer residual times atthe nerves, or a combination of both. After a desired dosage of thephotosensitizer has accumulated at the nerves, the photosensitizer canbe irradiated using contacts 824. The contacts 824 can deliver radiationto the target nerves at a wavelength that causes the photosensitizer toreact such that it damages or disrupts the nerves. For example, thephotosensitizer can become toxic upon exposure to the radiation. Becausethe photosensitizer preferentially accumulates at the nerves and not theother tissue proximate the nerves, the toxicity and corresponding damageis localized primarily at the nerves. This form of irradiativeneuromodulation can also or alternatively be incorporated in any one ofthe neuromodulation assemblies described herein. Further details andcharacteristics of neuromodulation assemblies with radiation emittersare included in U.S. patent application Ser. No. 13/826,604, which isincorporated herein by reference in its entirety.

FIG. 9 is a side view of a neuromodulation assembly 920 at a distalportion of a neuromodulation catheter configured in accordance with afurther embodiment of the present technology. The neuromodulationassembly 920 includes various features generally similar to the featuresof the neuromodulation assemblies 120, 720 and 820 described above. Forexample, the neuromodulation assembly 920 can be attached to a distalportion 908 b of a shaft 908, and can include a plurality of contacts924 configured to be placed into contact with a vessel wall V when theneuromodulation assembly 920 is deployed within a vessel (e.g., FIG. 9).In the embodiment illustrated in FIG. 9, the contacts 924 are carried byan outer expandable body 962 (e.g., a balloon) that positions thecontacts 924 against a vessel wall V when the expandable body 962 isdeployed (e.g., inflated or otherwise expanded) within the vessel. Inaddition, the neuromodulation assembly 920 can include a digitizer 928carried by the distal portion 908 b of the shaft 908 and communicativelycoupled to the contacts 924. At least some of the contacts 924 carriedby the expandable body 962 can be communicatively coupled to thedigitizer 828 via signal wires or a wireless coupling means such thatthe digitizer 928 can receive the analog signals recorded by thecontacts 924, filter and digitize the analog signals, and transmit thedigitized neural signals to an extracorporeal device via a wired orwireless connection. In other embodiments, one or more digitizers 928can be carried by the expandable body 962, and can include contacts thatrecord analog neural signals when placed in contact with the vessel wallV. In other embodiments, one or more digitizers 928 can be positionedelsewhere on the neuromodulation assembly 920.

As shown in FIG. 9, the shaft 908 and/or another suitable elongatedmember connected to the shaft 908 can extend at least partially throughthe expandable body 962 and carry an ultrasound transducer 964. Theultrasound transducer 964 may be configured to provide therapeuticallyeffective energy (e.g., HIFU) and, optionally, provide imaginginformation that may facilitate placement of the transducer 964 relativeto a blood vessel, optimize energy delivery, and/or provide tissuefeedback (e.g. to determine when treatment is complete). Further,depending on the particular arrangement of the ultrasound transducer964, the lesion created by the application of ultrasound energy may belimited to very specific areas (e.g., focal zones or focal points) onthe periphery of the vessel wall V or on the nerves themselves. Forexample, it is expected that the average ultrasound intensity for neuralmodulation (e.g., ablation of renal nerves) may be in the range of about1-4 kW/cm² and may be delivered for a total of 10-60 seconds to createone focal lesion.

In the embodiment illustrated in FIG. 9, the neuromodulation assembly920 further includes an inner expandable body 966 (e.g., a balloon)positioned within the outer expandable body 962 and around theultrasound transducer 964. The inner expandable body 966 can be filledwith a sound-conducting medium (e.g. water, a conductive medium, etc.)and act as an acoustic lens and transmission media for the emittedultrasonic energy. As indicated by the arrows, the waves emitted by theultrasound transducer 964 can be formed into one or more focal beamsfocusing on corresponding focal points or regions 968 (e.g., about 0-5mm deep in the surrounding tissue). In other embodiments, other features(e.g., an acoustically reflective material) can be used to form thewaves into one or more focal beams.

As shown in FIG. 9, the outer expandable body 962 may be configured toposition the contacts 924 away from the waves emitted by the ultrasoundtransducer 964 to avoid undesirably heating the contacts 924.Optionally, the outer expandable body 962 can be filled with a gas tocontain the energy emitted by the ultrasound transducer 964 and inhibitit from escaping in the undesired directions. This form ofultrasound-based neuromodulation can also or alternatively beincorporated in any one of the neuromodulation assemblies describedabove or below. Additional features and alternative embodiments ofultrasound-induced neuromodulation devices are disclosed in U.S. patentapplication Ser. No. 12/940,0922 (U.S. Patent Publication No.2011/0112400), which is incorporated herein by reference in itsentirety.

FIG. 10 is a partial cross-sectional side view of a neuromodulationassembly 1020 at a distal portion of a neuromodulation catheterconfigured in accordance with yet another embodiment of the presenttechnology. The neuromodulation assembly 1020 includes various featuresgenerally similar to the features of the neuromodulation assemblies 120,720, 820 and 920 described above. For example, the neuromodulationassembly 1020 can be attached to a distal portion 1008 b of a shaft1008, and can include a plurality of contacts 1024 configured to beplaced into contact with a vessel wall V when the neuromodulationassembly 1020 is deployed within a vessel (e.g., FIG. 10). As shown inFIG. 10, the contacts 1024 can be electrically coupled to correspondingconductive leads 1070 (e.g., electrical wires) that extend through oralong the shaft 1008. The leads 1070 can operably couple the contacts1024 to an energy source (e.g., the energy generator 126 of FIG. 1)and/or a digitizer 1028 at the distal portion 1008 b of the shaft 1008.The digitizer 1028 can receive the analog signals recorded by thecontacts 1024, filter and digitize the analog signals, and transmit thedigitized neural signals to an extracorporeal device via a wired orwireless connection.

As shown in FIG. 10, the neuromodulation assembly 1020 can furtherinclude a cryogenic applicator 1072 (e.g., a balloon or other expandablemember) that can expand radially outward to press or otherwise contactthe inner surface of the vessel wall V. For example, the cryogenicapplicator 1072 can define at least a portion of an expansion chamber inwhich a refrigerant expands or otherwise flows to provide cryogeniccooling. A supply lumen 1074 can be fluidly coupled to a refrigerantsource (e.g., a refrigerant cartridge or canister; not shown) at itsproximal end portion, and may be sized to retain at least a portion ofthe refrigerant that reaches the expansion chamber at a high pressureliquid state. The supply lumen 1074 can include one or more orifices oropenings 1076 from which refrigerant can expand into the expansionchamber, or refrigerant can be configured to expand from a distalopening of a capillary tube (not shown) extending from the supply lumen1074. In various embodiments, the openings 1076 may have across-sectional area less than that of the supply lumen 1074 to impedethe flow of refrigerant proximate the expansion chamber, therebyincreasing the pressure drop of the refrigerant entering the expansionchamber and concentrating the refrigeration power at the cryogenicapplicator 1072. For example, the openings 1076 can be sized relative tothe area and/or length of an exhaust lumen (e.g., defined by a distalportion of the shaft 1008) to provide a sufficient flow rate ofrefrigerant, produce a sufficient pressure drop when the refrigerantenters the expansion chamber, and allow for sufficient venting ofexpanded refrigerant through the shaft 1008 to establish and maintaincooling at the cryogenic applicator 1072.

In operation, a liquid refrigerant can expand into a gaseous phase as itpasses through the openings 1076 of the supply lumen 1074 into theexpansion chamber (defined by at least a portion of the cryogenicapplicator 1072), thereby inflating the cryogenic applicator 1072. Theexpansion of the refrigerant causes a temperature drop in the expansionchamber, thereby forming one or more cooling zones around at least aportion of the cryogenic applicator 1072. In various embodiments, thecooling zones created by the cryogenic applicator 1072 can providetherapeutically effective cooling to nerves proximate to the vessel wallV, while the contacts 1024 serve a nerve monitoring function. In otherembodiments, the contacts 1024 can be replaced a plurality of digitizers1028 can be carried by the exterior surface of the cryogenic applicator1072, and can include contacts that record analog neural signals whenplaced in contact with the vessel wall V. In further embodiments, thecryogenic applicator 1072 can be a non-expandable member, such acryoprobe at the distal portion 1008 b of the shaft 1008 (e.g., aFREEZOR catheter available from Medtronic, Inc. of Minneapolis, Minn.).

In additional embodiments, the contacts 1024 can be configured toprovide resistive heating in and/or at the tissue to raise thetemperatures at hyperthermic zones in the vessel wall V and thesurrounding neural fibers to provide therapeutically-effectiveneuromodulation, and the cryogenic applicator 1072 can be configured toform non-therapeutic cooling zones before, during, and/or after thedelivery of hyperthermic energy by the contacts 1024. For example,concurrently with the application of hyperthermic energy via thecontacts 1024, the cooling zone can be provided at a relatively lowrefrigeration power, e.g., a power less than that required to induceneuromodulation. The cooling zone can cool the contacts 1024 and/or thebody tissue at or proximate to the target site (e.g., the inner surfaceof vessel wall V). The cooling zone provided by the cryogenic applicator1072 is expected to maintain lower temperatures, and thereby reducethermal trauma in the tissue proximate the inner surface of the vesselwall V during hyperthermic neuromodulation. The hyperthermic zone mayalso extend or focus more on the exterior area of the vessel wall Vwhere the nerves reside. Therefore, the neuromodulation assembly 1020can provide a reverse thermal gradient across a portion of the vesselwall V to provide hyperthermic neuromodulation at a depth in the tissue,while reducing potential hyperthermal effects on the vessel tissuecloser to the neuromodulation assembly 1020.

The cryotherapeutic neuromodulation and/or cryogenic cooling describedabove can also or alternatively be incorporated in any one of theneuromodulation assemblies described above. Further details andcharacteristics of neuromodulation assemblies with cryogenic applicatorsare included in International Patent Application No. PCT/US2011/057514and U.S. patent application Ser. No. 13/458,859, each of which isincorporated herein by reference in its entirety.

FIG. 11 is a side view of a neuromodulation assembly 1120 at a distalportion of a neuromodulation catheter configured in accordance with yetanother embodiment of the present technology. The neuromodulationassembly 1120 includes various features generally similar to thefeatures of the neuromodulation assemblies 120, 720, 820, 920 and 1020described above. For example, the neuromodulation assembly 1120 can beattached to a distal portion 1108 b of a shaft 1108, and can include aplurality of contacts 1124 configured to be placed into contactproximate to a vessel wall V when the neuromodulation assembly 1120 isdeployed within a vessel. As shown in FIG. 11, the neuromodulationassembly 1120 can further include a balloon 1180 or other expandablemember that carries the contacts 1124. The balloon 1180 can be inflatedwith a fluid to place the contacts 1124 in contact with the vessel wallV and, optionally, occlude the vessel. For example, the balloon 1180 canbe inflated by injecting a gas into the balloon 1180 via an inflationlumen (not shown) that extends along the length of the shaft 1108. Inother embodiments, a fluid (e.g., a gas, a cryogenic fluid) can becirculated through the balloon 1180 to inflate the device.

As shown in FIG. 11, each contact 1124 can be a bipolar element havingone or more oppositely biased contact pairs. For example, the contacts1124 can each have a row of positive contacts 1125 a and a row ofnegative contacts 1125 b. In operation, a small electrical field isestablished between the positive contacts 1125 a and the negativecontacts 1125 b. Each contact 1124 can also include a thermistor 1126.The contacts 1124 with the various contacts 1125 a-b and thermistors1126 can be flex circuits attached to a balloon 1180 or printed directlyonto the balloon 1080.

The neuromodulation assembly 1120 can include a digitizer 1128 carriedby the distal portion 1108 b of the shaft 1108 and communicativelycoupled to the contacts 1124. At least some of the contacts 1124 carriedby the balloon 1180 can be communicatively coupled to the digitizer 128such that the digitizer 1128 can receive the analog signals recorded bythe contacts 1124, filter and digitize the analog signals, and transmitthe digitized neural signals to an extracorporeal device via a wired orwireless connection. In other embodiments, one or more digitizers 1128can be carried by the balloon 1180, and can include contacts that recordanalog neural signals when placed in contact with the vessel wall V. Inother embodiments, one or more digitizers 1128 can be positionedelsewhere on the neuromodulation assembly 1120.

As further shown in FIG. 11, the plurality of contacts 1124 can beelectrically coupled to a corresponding plurality of leads 1170 that arecoupled to or positioned about the expandable member 1180. In variousembodiments, the leads 1170 can be part of a flex circuit that easilyexpands or collapses with the expandable member 1180. The leads 1170 canbe electrically coupled to an energy source (e.g., the energy generator126 of FIG. 1) and/or the digitizer 1128 at the distal portion 1108 b ofthe shaft 1108. Accordingly, the contacts 1124 can provide both a nerverecording function and a neuromodulation function.

In the embodiment illustrated in FIG. 11, the contacts 1124 are definedby individual bipolar point electrodes that are spaced at multiplelengthwise and angular positions relative to the outer surface of theballoon 1180 and the vessel wall V. For example, the four contacts 1124shown in FIG. 11 can be angularly offset from each other by about 90°.In other embodiments, the contacts 1124 can be angularly offset fromeach other by different degrees (e.g., 60°, 80°, 180°, etc.) dependingon the number of contacts 1124 and/or their relative spacing along thelength of the balloon 1180. The lengthwise and/or angularly offsetcontacts 1124 can provide non-continuous circumferential neuromodulationand/or neural recording without having to reposition the neuromodulationassembly 1120. The illustrated embodiment shows four contacts 1124, butother embodiments can include different numbers of contacts (e.g., 1-12contacts 1124). In further embodiments, the contacts 1124 can have othersuitable configurations on the outer surface of the balloon 1180, and/orthe contacts 1124 may have other suitable structures. For example, incertain embodiments one or more of the contacts 1124 can be defined bycircular electrodes and/or spiral-shaped electrodes that extend aroundthe outer surface of the balloon 1180. Such configurations can providepartial or full circumferential neuromodulation and/or neural recordingalong the vessel wall V.

III. RENAL NEUROMODULATION

Renal neuromodulation is the partial or complete incapacitation or othereffective disruption of nerves of the kidneys (e.g., nerves terminatingin the kidneys or in structures closely associated with the kidneys). Inparticular, renal neuromodulation can include inhibiting, reducing,and/or blocking neural communication along neural fibers (e.g., efferentand/or afferent neural fibers) of the kidneys. Such incapacitation canbe long-term (e.g., permanent or for periods of months, years, ordecades) or short-term (e.g., for periods of minutes, hours, days, orweeks). Renal neuromodulation is expected to contribute to the systemicreduction of sympathetic tone or drive and/or to benefit at least somespecific organs and/or other bodily structures innervated by sympatheticnerves. Accordingly, renal neuromodulation is expected to be useful intreating clinical conditions associated with systemic sympatheticoveractivity or hyperactivity, particularly conditions associated withcentral sympathetic overstimulation. For example, renal neuromodulationis expected to efficaciously treat hypertension, heart failure, acutemyocardial infarction, metabolic syndrome, insulin resistance, diabetes,left ventricular hypertrophy, chronic and end stage renal disease,inappropriate fluid retention in heart failure, cardio-renal syndrome,polycystic kidney disease, polycystic ovary syndrome, osteoporosis,erectile dysfunction, and sudden death, among other conditions.

Renal neuromodulation can be electrically-induced, thermally-induced,chemically-induced, or induced in another suitable manner or combinationof manners at one or more suitable target sites during a treatmentprocedure. The target site can be within or otherwise proximate to arenal lumen (e.g., a renal artery, a ureter, a renal pelvis, a majorrenal calyx, a minor renal calyx, or another suitable structure), andthe treated tissue can include tissue at least proximate to a wall ofthe renal lumen. For example, with regard to a renal artery, a treatmentprocedure can include modulating nerves in the renal plexus, which layintimately within or adjacent to the adventitia of the renal artery.

Renal neuromodulation can include a cryotherapeutic treatment modalityalone or in combination with another treatment modality. Cryotherapeutictreatment can include cooling tissue at a target site in a manner thatmodulates neural function. For example, sufficiently cooling at least aportion of a sympathetic renal nerve can slow or potentially blockconduction of neural signals to produce a prolonged or permanentreduction in renal sympathetic activity. This effect can occur as aresult of cryotherapeutic tissue damage, which can include, for example,direct cell injury (e.g., necrosis), vascular or luminal injury (e.g.,starving cells from nutrients by damaging supplying blood vessels),and/or sublethal hypothermia with subsequent apoptosis. Exposure tocryotherapeutic cooling can cause acute cell death (e.g., immediatelyafter exposure) and/or delayed cell death (e.g., during tissue thawingand subsequent hyperperfusion). Neuromodulation using a cryotherapeutictreatment in accordance with embodiments of the present technology caninclude cooling a structure proximate an inner surface of a body lumenwall such that tissue is effectively cooled to a depth where sympatheticrenal nerves reside. For example, in some embodiments, a coolingassembly of a cryotherapeutic device can be cooled to the extent that itcauses therapeutically-effective, cryogenic renal neuromodulation. Inother embodiments, a cryotherapeutic treatment modality can includecooling that is not configured to cause neuromodulation. For example,the cooling can be at or above cryogenic temperatures and can be used tocontrol neuromodulation via another treatment modality (e.g., to protecttissue from neuromodulating energy).

Renal neuromodulation can include an electrode-based or transducer-basedtreatment modality alone or in combination with another treatmentmodality. Electrode-based or transducer-based treatment can includedelivering electricity and/or another form of energy to tissue at atreatment location to stimulate and/or heat the tissue in a manner thatmodulates neural function. For example, sufficiently stimulating and/orheating at least a portion of a sympathetic renal nerve can slow orpotentially block conduction of neural signals to produce a prolonged orpermanent reduction in renal sympathetic activity. A variety of suitabletypes of energy can be used to stimulate and/or heat tissue at atreatment location. For example, neuromodulation in accordance withembodiments of the present technology can include delivering RF energy,pulsed energy, microwave energy, optical energy, focused ultrasoundenergy (e.g., high-intensity focused ultrasound energy), or anothersuitable type of energy alone or in combination. An electrode ortransducer used to deliver this energy can be used alone or with otherelectrodes or transducers in a multi-electrode or multi-transducerarray. Furthermore, the energy can be applied from within the body(e.g., within the vasculature or other body lumens in a catheter-basedapproach) and/or from outside the body (e.g., via an applicatorpositioned outside the body). Furthermore, energy can be used to reducedamage to non-targeted tissue when targeted tissue adjacent to thenon-targeted tissue is subjected to neuromodulating cooling.

Neuromodulation using focused ultrasound energy (e.g., high-intensityfocused ultrasound energy) can be beneficial relative to neuromodulationusing other treatment modalities. Focused ultrasound is an example of atransducer-based treatment modality that can be delivered from outsidethe body. Focused ultrasound treatment can be performed in closeassociation with imaging (e.g., magnetic resonance, computed tomography,fluoroscopy, ultrasound (e.g., intravascular or intraluminal), opticalcoherence tomography, or another suitable imaging modality). Forexample, imaging can be used to identify an anatomical position of atreatment location (e.g., as a set of coordinates relative to areference point). The coordinates can then entered into a focusedultrasound device configured to change the power, angle, phase, or othersuitable parameters to generate an ultrasound focal zone at the locationcorresponding to the coordinates. The focal zone can be small enough tolocalize therapeutically-effective heating at the treatment locationwhile partially or fully avoiding potentially harmful disruption ofnearby structures. To generate the focal zone, the ultrasound device canbe configured to pass ultrasound energy through a lens, and/or theultrasound energy can be generated by a curved transducer or by multipletransducers in a phased array (curved or straight).

Heating effects of electrode-based or transducer-based treatment caninclude ablation and/or non-ablative alteration or damage (e.g., viasustained heating and/or resistive heating). For example, a treatmentprocedure can include raising the temperature of target neural fibers toa target temperature above a first threshold to achieve non-ablativealteration, or above a second, higher threshold to achieve ablation. Thetarget temperature can be higher than about body temperature (e.g.,about 37° C.) but less than about 45° C. for non-ablative alteration,and the target temperature can be higher than about 45° C. for ablation.Heating tissue to a temperature between about body temperature and about45° C. can induce non-ablative alteration, for example, via moderateheating of target neural fibers or of vascular or luminal structuresthat perfuse the target neural fibers. In cases where vascularstructures are affected, the target neural fibers can be deniedperfusion resulting in necrosis of the neural tissue. Heating tissue toa target temperature higher than about 45° C. (e.g., higher than about60° C.) can induce ablation, for example, via substantial heating oftarget neural fibers or of vascular or luminal structures that perfusethe target fibers. In some patients, it can be desirable to heat tissueto temperatures that are sufficient to ablate the target neural fibersor the vascular or luminal structures, but that are less than about 90°C. (e.g., less than about 85° C., less than about 80° C., or less thanabout 75° C.).

Renal neuromodulation can include a chemical-based treatment modalityalone or in combination with another treatment modality. Neuromodulationusing chemical-based treatment can include delivering one or morechemicals (e.g., drugs or other agents) to tissue at a treatmentlocation in a manner that modulates neural function. The chemical, forexample, can be selected to affect the treatment location generally orto selectively affect some structures at the treatment location overother structures. The chemical, for example, can be guanethidine,ethanol, phenol, a neurotoxin, or another suitable agent selected toalter, damage, or disrupt nerves. A variety of suitable techniques canbe used to deliver chemicals to tissue at a treatment location. Forexample, chemicals can be delivered via one or more needles originatingoutside the body or within the vasculature or other body lumens. In anintravascular example, a catheter can be used to intravascularlyposition a therapeutic element including a plurality of needles (e.g.,micro-needles) that can be retracted or otherwise blocked prior todeployment. In other embodiments, a chemical can be introduced intotissue at a treatment location via simple diffusion through a body lumenwall, electrophoresis, or another suitable mechanism. Similar techniquescan be used to introduce chemicals that are not configured to causeneuromodulation, but rather to facilitate neuromodulation via anothertreatment modality.

III. RELATED ANATOMY AND PHYSIOLOGY

As noted previously, the sympathetic nervous system (SNS) is a branch ofthe autonomic nervous system along with the enteric nervous system andparasympathetic nervous system. It is always active at a basal level(called sympathetic tone) and becomes more active during times ofstress. Like other parts of the nervous system, the sympathetic nervoussystem operates through a series of interconnected neurons. Sympatheticneurons are frequently considered part of the peripheral nervous system(PNS), although many lie within the central nervous system (CNS).Sympathetic neurons of the spinal cord (which is part of the CNS)communicate with peripheral sympathetic neurons via a series ofsympathetic ganglia. Within the ganglia, spinal cord sympathetic neuronsjoin peripheral sympathetic neurons through synapses. Spinal cordsympathetic neurons are therefore called presynaptic (or preganglionic)neurons, while peripheral sympathetic neurons are called postsynaptic(or postganglionic) neurons.

At synapses within the sympathetic ganglia, preganglionic sympatheticneurons release acetylcholine, a chemical messenger that binds andactivates nicotinic acetylcholine receptors on postganglionic neurons.In response to this stimulus, postganglionic neurons principally releasenoradrenaline (norepinephrine). Prolonged activation may elicit therelease of adrenaline from the adrenal medulla.

Once released, norepinephrine and epinephrine bind adrenergic receptorson peripheral tissues. Binding to adrenergic receptors causes a neuronaland hormonal response. The physiologic manifestations include pupildilation, increased heart rate, occasional vomiting, and increased bloodpressure. Increased sweating is also seen due to binding of cholinergicreceptors of the sweat glands.

The sympathetic nervous system is responsible for up- anddown-regulating many homeostatic mechanisms in living organisms. Fibersfrom the SNS innervate tissues in almost every organ system, providingat least some regulatory function to physiological features as diverseas pupil diameter, gut motility, and urinary output. This response isalso known as sympatho-adrenal response of the body, as thepreganglionic sympathetic fibers that end in the adrenal medulla (butalso all other sympathetic fibers) secrete acetylcholine, whichactivates the secretion of adrenaline (epinephrine) and to a lesserextent noradrenaline (norepinephrine). Therefore, this response thatacts primarily on the cardiovascular system is mediated directly viaimpulses transmitted through the sympathetic nervous system andindirectly via catecholamines secreted from the adrenal medulla.

Science typically looks at the SNS as an automatic regulation system,that is, one that operates without the intervention of consciousthought. Some evolutionary theorists suggest that the sympatheticnervous system operated in early organisms to maintain survival as thesympathetic nervous system is responsible for priming the body foraction. One example of this priming is in the moments before waking, inwhich sympathetic outflow spontaneously increases in preparation foraction.

1. The Sympathetic Chain

As shown in FIG. 12, the SNS provides a network of nerves that allowsthe brain to communicate with the body. Sympathetic nerves originateinside the vertebral column, toward the middle of the spinal cord in theintermediolateral cell column (or lateral horn), beginning at the firstthoracic segment of the spinal cord and are thought to extend to thesecond or third lumbar segments. Because its cells begin in the thoracicand lumbar regions of the spinal cord, the SNS is said to have athoracolumbar outflow. Axons of these nerves leave the spinal cordthrough the anterior rootlet/root. They pass near the spinal (sensory)ganglion, where they enter the anterior rami of the spinal nerves.However, unlike somatic innervation, they quickly separate out throughwhite rami connectors which connect to either the paravertebral (whichlie near the vertebral column) or prevertebral (which lie near theaortic bifurcation) ganglia extending alongside the spinal column.

In order to reach the target organs and glands, the axons should travellong distances in the body, and, to accomplish this, many axons relaytheir message to a second cell through synaptic transmission. The endsof the axons link across a space, the synapse, to the dendrites of thesecond cell. The first cell (the presynaptic cell) sends aneurotransmitter across the synaptic cleft where it activates the secondcell (the postsynaptic cell). The message is then carried to the finaldestination.

In the SNS and other components of the peripheral nervous system, thesesynapses are made at sites called ganglia, discussed above. The cellthat sends its fiber is called a preganglionic cell, while the cellwhose fiber leaves the ganglion is called a postganglionic cell. Asmentioned previously, the preganglionic cells of the SNS are locatedbetween the first thoracic (T1) segment and third lumbar (L3) segmentsof the spinal cord. Postganglionic cells have their cell bodies in theganglia and send their axons to target organs or glands.

The ganglia include not just the sympathetic trunks but also thecervical ganglia (superior, middle and inferior), which sendssympathetic nerve fibers to the head and thorax organs, and the celiacand mesenteric ganglia (which send sympathetic fibers to the gut).

2. Innervation of the Kidneys

As FIG. 13 shows, the kidney is innervated by the renal plexus (RP),which is intimately associated with the renal artery. The renal plexus(RP) is an autonomic plexus that surrounds the renal artery and isembedded within the adventitia of the renal artery. The renal plexus(RP) extends along the renal artery until it arrives at the substance ofthe kidney. Fibers contributing to the renal plexus (RP) arise from theceliac ganglion, the superior mesenteric ganglion, the aorticorenalganglion and the aortic plexus. The renal plexus (RP), also referred toas the renal nerve, is predominantly comprised of sympatheticcomponents. There is no (or at least very minimal) parasympatheticinnervation of the kidney.

Preganglionic neuronal cell bodies are located in the intermediolateralcell column of the spinal cord. Preganglionic axons pass through theparavertebral ganglia (they do not synapse) to become the lessersplanchnic nerve, the least splanchnic nerve, first lumbar splanchnicnerve, second lumbar splanchnic nerve, and travel to the celiacganglion, the superior mesenteric ganglion, and the aorticorenalganglion. Postganglionic neuronal cell bodies exit the celiac ganglion,the superior mesenteric ganglion, and the aorticorenal ganglion to therenal plexus (RP) and are distributed to the renal vasculature.

3. Renal Sympathetic Neural Activity

Messages travel through the SNS in a bidirectional flow. Efferentmessages may trigger changes in different parts of the bodysimultaneously. For example, the sympathetic nervous system mayaccelerate heart rate; widen bronchial passages; decrease motility(movement) of the large intestine; constrict blood vessels; increaseperistalsis in the esophagus; cause pupil dilation, piloerection (goosebumps) and perspiration (sweating); and raise blood pressure. Afferentmessages carry signals from various organs and sensory receptors in thebody to other organs and, particularly, the brain.

Hypertension, heart failure and chronic kidney disease are a few of manydisease states that result from chronic activation of the SNS,especially the renal sympathetic nervous system. Chronic activation ofthe SNS is a maladaptive response that drives the progression of thesedisease states. Pharmaceutical management of therenin-angiotensin-aldosterone system (RAAS) has been a longstanding, butsomewhat ineffective, approach for reducing over-activity of the SNS.

As mentioned above, the renal sympathetic nervous system has beenidentified as a major contributor to the complex pathophysiology ofhypertension, states of volume overload (such as heart failure), andprogressive renal disease, both experimentally and in humans. Studiesemploying radiotracer dilution methodology to measure overflow ofnorepinephrine from the kidneys to plasma revealed increased renalnorepinephrine (NE) spillover rates in patients with essentialhypertension, particularly so in young hypertensive subjects, which inconcert with increased NE spillover from the heart, is consistent withthe hemodynamic profile typically seen in early hypertension andcharacterized by an increased heart rate, cardiac output, andrenovascular resistance. It is now known that essential hypertension iscommonly neurogenic, often accompanied by pronounced sympathetic nervoussystem overactivity.

Activation of cardiorenal sympathetic nerve activity is even morepronounced in heart failure, as demonstrated by an exaggerated increaseof NE overflow from the heart and the kidneys to plasma in this patientgroup. In line with this notion is the recent demonstration of a strongnegative predictive value of renal sympathetic activation on all-causemortality and heart transplantation in patients with congestive heartfailure, which is independent of overall sympathetic activity,glomerular filtration rate, and left ventricular ejection fraction.These findings support the notion that treatment regimens that aredesigned to reduce renal sympathetic stimulation have the potential toimprove survival in patients with heart failure.

Both chronic and end stage renal disease are characterized by heightenedsympathetic nervous activation. In patients with end stage renaldisease, plasma levels of norepinephrine above the median have beendemonstrated to be predictive for both all-cause death and death fromcardiovascular disease. This is also true for patients suffering fromdiabetic or contrast nephropathy. There is compelling evidencesuggesting that sensory afferent signals originating from the diseasedkidneys are major contributors to initiating and sustaining elevatedcentral sympathetic outflow in this patient group; this facilitates theoccurrence of the well known adverse consequences of chronic sympatheticover activity, such as hypertension, left ventricular hypertrophy,ventricular arrhythmias, sudden cardiac death, insulin resistance,diabetes, and metabolic syndrome.

(i) Renal Sympathetic Efferent Activity

Sympathetic nerves to the kidneys terminate in the blood vessels, thejuxtaglomerular apparatus and the renal tubules. Stimulation of therenal sympathetic nerves causes increased renin release, increasedsodium (Na⁺) reabsorption, and a reduction of renal blood flow. Thesecomponents of the neural regulation of renal function are considerablystimulated in disease states characterized by heightened sympathetictone and clearly contribute to the rise in blood pressure inhypertensive patients. The reduction of renal blood flow and glomerularfiltration rate as a result of renal sympathetic efferent stimulation islikely a cornerstone of the loss of renal function in cardio-renalsyndrome, which is renal dysfunction as a progressive complication ofchronic heart failure, with a clinical course that typically fluctuateswith the patient's clinical status and treatment. Pharmacologicstrategies to thwart the consequences of renal efferent sympatheticstimulation include centrally acting sympatholytic drugs, beta blockers(intended to reduce renin release), angiotensin converting enzymeinhibitors and receptor blockers (intended to block the action ofangiotensin II and aldosterone activation consequent to renin release)and diuretics (intended to counter the renal sympathetic mediated sodiumand water retention). However, the current pharmacologic strategies havesignificant limitations including limited efficacy, compliance issues,side effects and others.

(ii) Renal Sensory Afferent Nerve Activity

The kidneys communicate with integral structures in the central nervoussystem via renal sensory afferent nerves. Several forms of “renalinjury” may induce activation of sensory afferent signals. For example,renal ischemia, reduction in stroke volume or renal blood flow, or anabundance of adenosine enzyme may trigger activation of afferent neuralcommunication. As shown in FIGS. 14A and 14B, this afferentcommunication might be from the kidney to the brain or might be from onekidney to the other kidney (via the central nervous system). Theseafferent signals are centrally integrated and may result in increasedsympathetic outflow. This sympathetic drive is directed towards thekidneys, thereby activating the RAAS and inducing increased reninsecretion, sodium retention, volume retention and vasoconstriction.Central sympathetic over activity also impacts other organs and bodilystructures innervated by sympathetic nerves such as the heart and theperipheral vasculature, resulting in the described adverse effects ofsympathetic activation, several aspects of which also contribute to therise in blood pressure.

The physiology therefore suggests that (i) modulation of tissue withefferent sympathetic nerves will reduce inappropriate renin release,salt retention, and reduction of renal blood flow, and that (ii)modulation of tissue with afferent sensory nerves will reduce thesystemic contribution to hypertension and other disease statesassociated with increased central sympathetic tone through its directeffect on the posterior hypothalamus as well as the contralateralkidney. In addition to the central hypotensive effects of afferent renaldenervation, a desirable reduction of central sympathetic outflow tovarious other sympathetically innervated organs such as the heart andthe vasculature is anticipated.

B. Additional Clinical Benefits of Renal Denervation

As provided above, renal denervation is likely to be valuable in thetreatment of several clinical conditions characterized by increasedoverall and particularly renal sympathetic activity such ashypertension, metabolic syndrome, insulin resistance, diabetes, leftventricular hypertrophy, chronic end stage renal disease, inappropriatefluid retention in heart failure, cardio-renal syndrome, and suddendeath. Since the reduction of afferent neural signals contributes to thesystemic reduction of sympathetic tone/drive, renal denervation mightalso be useful in treating other conditions associated with systemicsympathetic hyperactivity. Accordingly, renal denervation may alsobenefit other organs and bodily structures innervated by sympatheticnerves, including those identified in FIG. 12. For example, aspreviously discussed, a reduction in central sympathetic drive mayreduce the insulin resistance that afflicts people with metabolicsyndrome and Type II diabetics. Additionally, patients with osteoporosisare also sympathetically activated and might also benefit from the downregulation of sympathetic drive that accompanies renal denervation.

C. Achieving Intravascular Access to the Renal Artery

In accordance with the present technology, neuromodulation of a leftand/or right renal plexus (RP), which is intimately associated with aleft and/or right renal artery, may be achieved through intravascularaccess. As FIG. 15A shows, blood moved by contractions of the heart isconveyed from the left ventricle of the heart by the aorta. The aortadescends through the thorax and branches into the left and right renalarteries. Below the renal arteries, the aorta bifurcates at the left andright iliac arteries. The left and right iliac arteries descend,respectively, through the left and right legs and join the left andright femoral arteries.

As FIG. 15B shows, the blood collects in veins and returns to the heart,through the femoral veins into the iliac veins and into the inferiorvena cava. The inferior vena cava branches into the left and right renalveins. Above the renal veins, the inferior vena cava ascends to conveyblood into the right atrium of the heart. From the right atrium, theblood is pumped through the right ventricle into the lungs, where it isoxygenated. From the lungs, the oxygenated blood is conveyed into theleft atrium. From the left atrium, the oxygenated blood is conveyed bythe left ventricle back to the aorta.

As will be described in greater detail later, the femoral artery may beaccessed and cannulated at the base of the femoral triangle justinferior to the midpoint of the inguinal ligament. A catheter may beinserted percutaneously into the femoral artery through this accesssite, passed through the iliac artery and aorta, and placed into eitherthe left or right renal artery. This comprises an intravascular paththat offers minimally invasive access to a respective renal arteryand/or other renal blood vessels.

The wrist, upper arm, and shoulder region provide other locations forintroduction of catheters into the arterial system. For example,catheterization of either the radial, brachial, or axillary artery maybe utilized in select cases. Catheters introduced via these accesspoints may be passed through the subclavian artery on the left side (orvia the subclavian and brachiocephalic arteries on the right side),through the aortic arch, down the descending aorta and into the renalarteries using standard angiographic technique.

D. Properties and Characteristics of the Renal Vasculature

Since neuromodulation of a left and/or right renal plexus (RP) may beachieved in accordance with the present technology through intravascularaccess, properties and characteristics of the renal vasculature mayimpose constraints upon and/or inform the design of apparatus, systems,and methods for achieving such renal neuromodulation. Some of theseproperties and characteristics may vary across the patient populationand/or within a specific patient across time, as well as in response todisease states, such as hypertension, chronic kidney disease, vasculardisease, end-stage renal disease, insulin resistance, diabetes,metabolic syndrome, etc. These properties and characteristics, asexplained herein, may have bearing on the efficacy of the procedure andthe specific design of the intravascular device. Properties of interestmay include, for example, material/mechanical, spatial, fluiddynamic/hemodynamic and/or thermodynamic properties.

As discussed previously, a catheter may be advanced percutaneously intoeither the left or right renal artery via a minimally invasiveintravascular path. However, minimally invasive renal arterial accessmay be challenging, for example, because as compared to some otherarteries that are routinely accessed using catheters, the renal arteriesare often extremely tortuous, may be of relatively small diameter,and/or may be of relatively short length. Furthermore, renal arterialatherosclerosis is common in many patients, particularly those withcardiovascular disease. Renal arterial anatomy also may varysignificantly from patient to patient, which further complicatesminimally invasive access. Significant inter-patient variation may beseen, for example, in relative tortuosity, diameter, length, and/oratherosclerotic plaque burden, as well as in the take-off angle at whicha renal artery branches from the aorta. Apparatus, systems and methodsfor achieving renal neuromodulation via intravascular access shouldaccount for these and other aspects of renal arterial anatomy and itsvariation across the patient population when minimally invasivelyaccessing a renal artery.

In addition to complicating renal arterial access, specifics of therenal anatomy also complicate establishment of stable contact betweenneuromodulatory apparatus and a luminal surface or wall of a renalartery. For example, navigation can be impeded by the tight space withina renal artery, as well as tortuosity of the artery. Furthermore,establishing consistent contact is complicated by patient movement,respiration, and/or the cardiac cycle because these factors may causesignificant movement of the renal artery relative to the aorta, and thecardiac cycle may transiently distend the renal artery (i.e. cause thewall of the artery to pulse).

Even after accessing a renal artery and facilitating stable contactbetween neuromodulatory apparatus and a luminal surface of the artery,nerves in and around the adventia of the artery should be safelymodulated via the neuromodulatory apparatus. Effectively applyingthermal treatment from within a renal artery is non-trivial given thepotential clinical complications associated with such treatment. Forexample, the intima and media of the renal artery are highly vulnerableto thermal injury. As discussed in greater detail below, theintima-media thickness separating the vessel lumen from its adventitiameans that target renal nerves may be multiple millimeters distant fromthe luminal surface of the artery. Sufficient energy should be deliveredto or heat removed from the target renal nerves to modulate the targetrenal nerves without excessively cooling or heating the vessel wall tothe extent that the wall is frozen, desiccated, or otherwise potentiallyaffected to an undesirable extent. A potential clinical complicationassociated with excessive heating is thrombus formation from coagulatingblood flowing through the artery. Given that this thrombus may cause akidney infarct, thereby causing irreversible damage to the kidney,thermal treatment from within the renal artery should be appliedcarefully. Accordingly, the complex fluid mechanics and thermodynamicconditions present in the renal artery during treatment, particularlythose that may impact heat transfer dynamics at the treatment site, maybe important in applying energy (e.g., heating thermal energy) and/orremoving heat from the tissue (e.g., cooling thermal conditions) fromwithin the renal artery.

The neuromodulatory apparatus should also be configured to allow foradjustable positioning and repositioning of the energy delivery elementwithin the renal artery since location of treatment may also impactclinical efficacy. For example, it may be tempting to apply a fullcircumferential treatment from within the renal artery given that therenal nerves may be spaced circumferentially around a renal artery. Insome situations, a full-circle lesion likely resulting from a continuouscircumferential treatment may be potentially related to renal arterystenosis. Therefore, the formation of more complex lesions along alongitudinal dimension of the renal artery and/or repositioning of theneuromodulatory apparatus to multiple treatment locations may bedesirable. It should be noted, however, that a benefit of creating acircumferential ablation may outweigh the potential of renal arterystenosis or the risk may be mitigated with certain embodiments or incertain patients and creating a circumferential ablation could be agoal. Additionally, variable positioning and repositioning of theneuromodulatory apparatus may prove to be useful in circumstances wherethe renal artery is particularly tortuous or where there are proximalbranch vessels off the renal artery main vessel, making treatment incertain locations challenging. Manipulation of a device in a renalartery should also consider mechanical injury imposed by the device onthe renal artery. Motion of a device in an artery, for example byinserting, manipulating, negotiating bends and so forth, may contributeto dissection, perforation, denuding intima, or disrupting the interiorelastic lamina.

Blood flow through a renal artery may be temporarily occluded for ashort time with minimal or no complications. However, occlusion for asignificant amount of time should be avoided because to prevent injuryto the kidney such as ischemia. It could be beneficial to avoidocclusion all together or, if occlusion is beneficial to the embodiment,to limit the duration of occlusion, for example to 2-5 minutes.

Based on the above described challenges of (1) renal arteryintervention, (2) consistent and stable placement of the treatmentelement against the vessel wall, (3) effective application of treatmentacross the vessel wall, (4) positioning and potentially repositioningthe treatment apparatus to allow for multiple treatment locations, and(5) avoiding or limiting duration of blood flow occlusion, variousindependent and dependent properties of the renal vasculature that maybe of interest include, for example, (a) vessel diameter, vessel length,intima-media thickness, coefficient of friction, and tortuosity; (b)distensibility, stiffness and modulus of elasticity of the vessel wall;(c) peak systolic, end-diastolic blood flow velocity, as well as themean systolic-diastolic peak blood flow velocity, and mean/maxvolumetric blood flow rate; (d) specific heat capacity of blood and/orof the vessel wall, thermal conductivity of blood and/or of the vesselwall, and/or thermal convectivity of blood flow past a vessel walltreatment site and/or radiative heat transfer; (e) renal artery motionrelative to the aorta induced by respiration, patient movement, and/orblood flow pulsatility; and (f) the take-off angle of a renal arteryrelative to the aorta. These properties will be discussed in greaterdetail with respect to the renal arteries. However, dependent on theapparatus, systems and methods utilized to achieve renalneuromodulation, such properties of the renal arteries, also may guideand/or constrain design characteristics.

As noted above, an apparatus positioned within a renal artery shouldconform to the geometry of the artery. Renal artery vessel diameter,D_(RA), typically is in a range of about 2-10 mm, with most of thepatient population having a D_(RA) of about 4 mm to about 8 mm and anaverage of about 6 mm. Renal artery vessel length, L_(RA), between itsostium at the aorta/renal artery juncture and its distal branchings,generally is in a range of about 5-70 mm, and a significant portion ofthe patient population is in a range of about 20-50 mm. Since the targetrenal plexus is embedded within the adventitia of the renal artery, thecomposite Intima-Media Thickness, IMT, (i.e., the radial outwarddistance from the artery's luminal surface to the adventitia containingtarget neural structures) also is notable and generally is in a range ofabout 0.5-2.5 mm, with an average of about 1.5 mm. Although a certaindepth of treatment is important to reach the target neural fibers, thetreatment should not be too deep (e.g., >5 mm from inner wall of therenal artery) to avoid non-target tissue and anatomical structures suchas the renal vein.

An additional property of the renal artery that may be of interest isthe degree of renal motion relative to the aorta induced by respirationand/or blood flow pulsatility. A patient's kidney, which is located atthe distal end of the renal artery, may move as much as 4″ craniallywith respiratory excursion. This may impart significant motion to therenal artery connecting the aorta and the kidney, thereby requiring fromthe neuromodulatory apparatus a unique balance of stiffness andflexibility to maintain contact between the energy delivery element andthe vessel wall during cycles of respiration. Furthermore, the take-offangle between the renal artery and the aorta may vary significantlybetween patients, and also may vary dynamically within a patient, e.g.,due to kidney motion. The take-off angle generally may be in a range ofabout 30°-135°.

IV. ADDITIONAL EXAMPLES

1. A neuromodulation catheter, comprising:

-   -   a handle;    -   an elongated shaft attached to the handle, the shaft having a        distal portion and a proximal portion, wherein at least the        distal portion is configured to be moved within a lumen of a        blood vessel of a human patient;    -   an array of contacts at the distal portion of the shaft, wherein        the contacts are configured to detect analog neural signals from        nerves along the blood vessel while the contacts are within the        blood vessel; and    -   a digitizer at the handle or the shaft, wherein the digitizer is        configured to receive the analog neural signals from the        contacts, digitize the analog neural signals into digital neural        signals, and transmit the digital neural signals to a read/write        module external to the patient.

2. The neuromodulation catheter of example 1 wherein the digitizer is atthe distal portion of the elongated shaft.

3. The neuromodulation catheter of example 1 wherein the digitizer is atthe distal portion of the elongated shaft proximal to the contacts.

4. The neuromodulation catheter of example 1 wherein the digitizer is atthe handle.

5. The neuromodulation catheter of example 4 wherein the digitizer isconfigured to be detachable from the handle for reuse with otherneuromodulation catheters.

6. The neuromodulation catheter of example 1 wherein the digital neuralsignals comprise electroneurogram (ENG) signals, and wherein thedigitizer is configured to filter signals received from the contacts todifferentiate the ENG signals from electromyogram (EMG) signals beforetransmitting the digital neural signals to the read/write module.

7. The neuromodulation catheter of example 1 wherein the digitizer isconfigured to filer signals received from the contacts using anamplifier assembly having a quasi-tripole (QT), true-tripole (TT),and/or adaptive-tripole (AT) arrangement to detect electroneurogram(ENG) signals.

8. The neuromodulation catheter of example 1 wherein the digitizercomprises an analog to digital circuit.

9. The neuromodulation catheter of example 1 wherein the digitizer has across-sectional dimension of about 9-25 mm².

10. The neuromodulation catheter of example 1 wherein the digitizerfurther comprises a telemetry module configured to wirelessly transmitthe digitized signals from within the patient to the read/write module.

11. The neuromodulation catheter of example 1 wherein the digitizer isinductively coupled to the read-write module.

12. The neuromodulation catheter of example 1 wherein the digitizerincludes the contacts.

13. The neuromodulation catheter of example 12 wherein the digitizer isone of a plurality of digitizers, wherein each digitizer includes aplurality of contacts, and wherein the plurality of digitizers are atthe distal portion of the shaft.

14. The neuromodulation catheter of example 1, further comprising atleast one energy delivery element at the distal portion of the elongatedshaft, wherein the energy delivery element is configured to deliverneuromodulation energy to a target site within the blood vessel of thepatient.

15. The neuromodulation catheter of example 14 wherein the energydelivery element comprises a cryotherapeutic applicator, an ultrasounddelivery element, and/or an RF electrode.

16. The neuromodulation catheter of example 1 wherein the contacts arefurther configured to deliver neuromodulation energy the nerves alongthe blood vessel of the patient and detect the analog neural signalsbefore and/or after the delivery of the neuromodulation energy.

17. The neuromodulation catheter of example 1, further comprising asupport member at the distal portion of the shaft, wherein the supportmember has a spiral shape and is configured to contact an interior wallof the blood vessel when the support member is in a deployed state,wherein the contacts are spaced apart from each other along a length ofthe support member, and wherein the contacts are configured to deliverneuromodulation energy to the nerves along the blood vessel.

18. The neuromodulation catheter of example 1, further comprising aplurality of supports that define a basket structure at the distalportion of the shaft, wherein the contacts are arranged along thesupports and, and wherein the supports are configured to contact aninterior wall of the blood vessel when the supports are in a deployedstate.

19. The neuromodulation catheter of example 1, further comprising a meshstructure at the distal portion of the shaft, wherein the mesh structureis configured to contact an interior wall of the blood vessel when themesh structure is in a deployed state, and wherein the contacts arearranged along the mesh structure.

20. The neuromodulation catheter of example 1, further comprising aballoon at the distal portion of the shaft, wherein the balloon carriesthe contacts and is configured to place the contacts into contact withan interior wall of the blood vessel when expanded.

21. The neuromodulation catheter of example 1 wherein:

-   -   the digital neural signals comprise electroneurogram (ENG)        signals, and wherein the digitizer is configured to filter        signals received from the contacts to differentiate the ENG        signals from electromyogram (EMG) signals before transmitting        the digital neural signals to the read/write module; and    -   the digitizer further comprises a telemetry module configured to        wirelessly transmit the digitized signals from within the        patient to the read/write module.

22. The neuromodulation catheter of example 1 wherein:

-   -   the digitizer is at the distal portion of the elongated shaft        proximal to the contacts, wherein the digitizer chip comprises—        -   a telemetry module configured to wirelessly transmit the            digitized signals from within the patient to the read/write            module;        -   an analog to digital circuit; and        -   a amplifier assembly configured to filter signals received            from the contacts to differentiate the electroneurogram            (ENG) signals from electromyogram (EMG) signals before            transmitting the digital neural signals to the read/write            module; and    -   the contacts are further configured to deliver neuromodulation        energy to the nerves along the blood vessel of the patient and        detect the analog neural signals before and/or after the        delivery of the neuromodulation energy.

23. A neuromodulation catheter, comprising:

-   -   a shaft configured to be moved through a lumen of a blood vessel        of a human and having a distal portion and a proximal portion;    -   a plurality of contacts at the distal portion of the shaft,        wherein the contacts are configured to detect analog neural        measurements from within a blood vessel in a human; and    -   a digitizer electrically coupled to the contacts and attached to        the catheter at a location such that the amplitude of the analog        neural signals remains above a level at which the analog neural        signals can be accurately digitized from other signals detected        by the contacts, wherein the digitizer is configured to digitize        the analog neural measurements and produce digital neural        signals.

24. The catheter of example 23 wherein the digitizer is attached to theshaft of the catheter.

25. The catheter of example 23, further comprising a handle attached tothe shaft, wherein the digitizer is attached to the handle.

26. The catheter of example 23 wherein the digitizer comprises an analogto digital circuit configured to digitized the analog neural signals, amemory to store the digital neural signals, and a telemetry systemconfigured to transmit the digital neural signals to an extracorporealreceiver located outside of the human.

27. A neuromodulation system, comprising:

-   -   a neuromodulation catheter having a distal portion and a        proximal portion and configured to be moved through a lumen of a        blood vessel of a human, wherein the neuromodulation catheter        comprises—        -   a plurality of contacts configured to detect analog neural            measurements from within the blood vessel of the human; and        -   a digitizer operably coupled to the contacts, wherein the            digitizer is configured to digitize the analog neural            measurements and produce digital neural signals; and    -   a read/write module communicatively coupled to the digitizer and        configured to receive the digital signals of the neural        measurements.

28. The neuromodulation system of example 27 wherein the digitizer andthe read/write module are wirelessly coupled to each other.

29. The neuromodulation system of example 27 wherein contacts areintegrated with the digitizer.

30. The neuromodulation system of example 27 wherein the distal portionof the neuromodulation catheter comprises at least one energy deliveryelement configured to deliver to therapeutically-effectiveneuromodulation energy to neural fibers at a target site within theblood vessel of the human.

31. The neuromodulation system of example 30 wherein the contacts definethe at least one energy delivery element such that the contacts areconfigured to deliver neuromodulation energy to neural fibers and detectneural measurements before and after delivering the neuromodulationenergy.

32. The neuromodulation system of example 27 wherein the digitizer is atthe distal portion of the neuromodulation catheter proximate to thecontacts.

33. The neuromodulation system of example 27 wherein the digitizercomprises a amplifier assembly configured to filter signals receivedfrom the contacts to differentiate the electroneurogram (ENG) signalsfrom electromyogram (EMG) signals before transmitting digital neuralsignals to the read/write module.

34. A neuromodulation system, comprising:

-   -   a neuromodulation catheter having—        -   an elongated shaft having a distal portion and a proximal            portion, wherein at least the distal portion is configured            to be moved within a lumen of a blood vessel of a human;        -   an array of contacts at the distal portion of the shaft,            wherein the contacts are configured to detect analog neural            signals from within the blood vessel; and        -   a transmitter operably coupled to the contacts; and    -   a guide catheter configured to extend over the neuromodulation        catheter and deliver at least the distal portion of the shaft to        a target site within the blood vessel, wherein the guide        catheter comprises—        -   a digitizer configured to receive the analog neural signals            from the transmitter, digitize the analog neural signals            into digital neural signals, and transmit the digital neural            signals to a read/write module external to the human.

35. A method of detecting neural activity from within a blood vessel ofa human, the method comprising:

-   -   delivering a distal portion of a neuromodulation catheter to a        target site within the blood vessel of the human, wherein the        distal portion comprises a plurality of contacts;    -   recording analog neural signals with the contacts;    -   digitizing recorded analog neural signals via a digitizer        operably coupled to the contacts, wherein the digitizer is        integrated with the neuromodulation catheter; and    -   transmitting the digital neural signals to a read/write module        external to the human.

36. The method of example 35 wherein digitizing the recorded analogneural signals is performed within the human.

37. The method of example 35, further comprising filtering the recordedanalog neural signals with the digitizer to differentiateelectroneurogram (ENG) signals from electromyogram (EMG) signals.

38. The method of example 35, further comprising filtering the recordedanalog neural signals with the digitizer using quasi-tripole (QT),true-tripole (TT), and/or adaptive-tripole (AT) signal processingtechniques to detect electroneurogram (ENG) signals, wherein the analogneural signals are filtered before digitizing.

39. The method of example 35, further comprising:

-   -   delivering neuromodulation energy to a target site within the        blood vessel of the human via at least one energy delivery        element, wherein the recording, digitizing, and transmitting        steps are performed before and after delivery of the        neuromodulation energy; and    -   comparing electroneurogram (ENG) signals recorded before and        after delivery of the neuromodulation energy.

40. The method of example 39, further comprising deliveringneuromodulation energy at the target site for a second time when thereis not a decrease in the ENG signal detected after energy delivery.

41. The method of example 39 wherein the target site is a first targetsite, and wherein the method further comprises:

repositioning the energy delivery element to a second target site withinthe blood vessel; and

-   -   delivering neuromodulation energy to the second target site via        the energy delivery element, wherein the recording, digitizing,        and transmitting steps are performed before and after delivery        of the neuromodulation energy.

42. The method of example 35 wherein:

-   -   recording analog neural signals further comprises recording a        plurality of analog neural signals taken during a plurality of        different time intervals;    -   digitizing recorded analog neural signals further comprises        digitizing each of the recorded neural signals;    -   transmitting the digital neural signals to the read/write module        further comprises transmitting each of the digital neural        signals to the read/write module after each time interval; and    -   averaging the digital neural signals at the read/write module to        determine nerve activity proximate to the contacts.

43. The method of example 35, further comprising comparingelectroneurogram (ENG) signals taken at different time intervals.

44. The method of example 35 wherein transmitting the digital neuralsignals comprises wirelessly transmitting the digital neural signalsfrom within the human to the read/write module.

45. The method of example 35 wherein transmitting the digital neuralsignals comprises inductively transmitting the digital neural signalsfrom within the human to the read/write module.

46. The method of example 35 wherein the neuromodulation cathetercomprises a handle at the proximal portion of the neuromodulationcatheter, and wherein the digitizer is at the handle.

47. The method of example 35, further comprising deliveringneuromodulation energy via at least one energy delivery element to atarget site within the blood vessel of the human, wherein the recording,digitizing, and transmitting steps are performed before and/or afterdelivery of the neuromodulation energy.

48. The method of example 47 wherein delivering the neuromodulationenergy via the energy delivery element comprises delivering theneuromodulation energy via the plurality of contacts.

49. The method of example 47 wherein the energy delivery elementcomprises a radiation emitter, and wherein delivering neuromodulationenergy via the energy delivery element comprises delivering radiation toa vessel wall at the target site.

50. The method of example 47 wherein the energy delivery elementcomprises an ultrasound transducer, and wherein deliveringneuromodulation energy via the energy delivery element comprisesdelivering ultrasound waves to a vessel wall at the target site.

51. The method of example 47 wherein the energy delivery elementcomprises a cryotherapeutic applicator, and wherein deliveringneuromodulation energy via the energy delivery element comprisesdelivering cryotherapeutic cooling to a vessel wall at the target site.

52. A neuromodulation catheter, comprising:

-   -   a shaft configured to be moved through a lumen of a blood vessel        of a human and having a distal portion from which therapeutic        energy is delivered to a target site within the blood vessel;        and    -   a digitizer at the distal portion of the shaft and having a        plurality of contacts, wherein the contacts are configured to        detect analog neural measurements from within a blood vessel in        a human, and wherein the digitizer is configured to digitize the        analog neural measurements and produce digital neural signals.

53. The neuromodulation catheter of claim 52 wherein the contacts areconfigured to deliver the therapeutic energy to the target site.

54. The neuromodulation catheter of example 52 wherein the digitizer isone of a plurality of digitizers at the distal portion of the shaft.

55. The neuromodulation catheter of example 52 wherein the digitizercomprises an analog to digital circuit configured to digitize the analogneural signals, a memory to store the digital neural signals, and atelemetry system configured to transmit the digital neural signals to anextracorporeal receiver located outside of the human.

V. CONCLUSION

This disclosure is not intended to be exhaustive or to limit the presenttechnology to the precise forms disclosed herein. Although specificembodiments are disclosed herein for illustrative purposes, variousequivalent modifications are possible without deviating from the presenttechnology, as those of ordinary skill in the relevant art willrecognize. In some cases, well-known structures and functions have notbeen shown and/or described in detail to avoid unnecessarily obscuringthe description of the embodiments of the present technology. Althoughsteps of methods may be presented herein in a particular order, inalternative embodiments the steps may have another suitable order.Similarly, certain aspects of the present technology disclosed in thecontext of particular embodiments can be combined or eliminated in otherembodiments. Furthermore, while advantages associated with certainembodiments may have been disclosed in the context of those embodiments,other embodiments can also exhibit such advantages, and not allembodiments need necessarily exhibit such advantages or other advantagesdisclosed herein to fall within the scope of the present technology.Accordingly, this disclosure and associated technology can encompassother embodiments not expressly shown and/or described herein.

Throughout this disclosure, the singular terms “a,” “an,” and “the”include plural referents unless the context clearly indicates otherwise.Similarly, unless the word “or” is expressly limited to mean only asingle item exclusive from the other items in reference to a list of twoor more items, then the use of “or” in such a list is to be interpretedas including (a) any single item in the list, (b) all of the items inthe list, or (c) any combination of the items in the list. Additionally,the terms “comprising” and the like are used throughout this disclosureto mean including at least the recited feature(s) such that any greaternumber of the same feature(s) and/or one or more additional types offeatures are not precluded. Directional terms, such as “upper,” “lower,”“front,” “back,” “vertical,” and “horizontal,” may be used herein toexpress and clarify the relationship between various elements. It shouldbe understood that such terms do not denote absolute orientation.Reference herein to “one embodiment,” “an embodiment,” or similarformulations means that a particular feature, structure, operation, orcharacteristic described in connection with the embodiment can beincluded in at least one embodiment of the present technology. Thus, theappearances of such phrases or formulations herein are not necessarilyall referring to the same embodiment. Furthermore, various particularfeatures, structures, operations, or characteristics may be combined inany suitable manner in one or more embodiments.

I/We claim:
 1. A neuromodulation catheter, comprising: a handle; anelongated shaft attached to the handle, the shaft having a distalportion and a proximal portion, wherein at least the distal portion isconfigured to be moved within a lumen of a blood vessel of a humanpatient; an array of contacts at the distal portion of the shaft,wherein the contacts are configured to detect analog neural signals fromnerves along the blood vessel while the contacts are within the bloodvessel; and a digitizer at the handle or the shaft, wherein thedigitizer is configured to receive the analog neural signals from thecontacts, digitize the analog neural signals into digital neuralsignals, and transmit the digital neural signals to a read/write moduleexternal to the patient.
 2. The neuromodulation catheter of claim 1wherein the digitizer is at the distal portion of the elongated shaft.3. The neuromodulation catheter of claim 1 wherein the digitizer is atthe distal portion of the elongated shaft proximal to the contacts. 4.The neuromodulation catheter of claim 1 wherein the digitizer is at thehandle.
 5. The neuromodulation catheter of claim 4 wherein the digitizeris configured to be detachable from the handle for reuse with otherneuromodulation catheters.
 6. The neuromodulation catheter of claim 1wherein the digital neural signals comprise electroneurogram (ENG)signals, and wherein the digitizer is configured to filter signalsreceived from the contacts to differentiate the ENG signals fromelectromyogram (EMG) signals before transmitting the digital neuralsignals to the read/write module.
 7. The neuromodulation catheter ofclaim 1 wherein the digitizer is configured to filer signals receivedfrom the contacts using an amplifier assembly having a quasi-tripole(QT), true-tripole (TT), and/or adaptive-tripole (AT) arrangement todetect electroneurogram (ENG) signals.
 8. The neuromodulation catheterof claim 1 wherein the digitizer comprises an analog to digital circuit.9. The neuromodulation catheter of claim 1 wherein the digitizer has across-sectional dimension of about 9-25 mm².
 10. The neuromodulationcatheter of claim 1 wherein the digitizer further comprises a telemetrymodule configured to wirelessly transmit the digitized signals fromwithin the patient to the read/write module.
 11. The neuromodulationcatheter of claim 1 wherein the digitizer is inductively coupled to theread-write module.
 12. The neuromodulation catheter of claim 1 whereinthe digitizer includes the contacts.
 13. The neuromodulation catheter ofclaim 12 wherein the digitizer is one of a plurality of digitizers,wherein each digitizer includes a plurality of contacts, and wherein theplurality of digitizers are at the distal portion of the shaft.
 14. Theneuromodulation catheter of claim 1, further comprising at least oneenergy delivery element at the distal portion of the elongated shaft,wherein the energy delivery element is configured to deliverneuromodulation energy to a target site within the blood vessel of thepatient.
 15. The neuromodulation catheter of claim 14 wherein the energydelivery element comprises a cryotherapeutic applicator, an ultrasounddelivery element, and/or an RF electrode.
 16. The neuromodulationcatheter of claim 1 wherein the contacts are further configured todeliver neuromodulation energy the nerves along the blood vessel of thepatient and detect the analog neural signals before and/or after thedelivery of the neuromodulation energy.
 17. The neuromodulation catheterof claim 1, further comprising a support member at the distal portion ofthe shaft, wherein the support member has a spiral shape and isconfigured to contact an interior wall of the blood vessel when thesupport member is in a deployed state, wherein the contacts are spacedapart from each other along a length of the support member, and whereinthe contacts are configured to deliver neuromodulation energy to thenerves along the blood vessel.
 18. The neuromodulation catheter of claim1, further comprising a plurality of supports that define a basketstructure at the distal portion of the shaft, wherein the contacts arearranged along the supports and, and wherein the supports are configuredto contact an interior wall of the blood vessel when the supports are ina deployed state.
 19. The neuromodulation catheter of claim 1, furthercomprising a mesh structure at the distal portion of the shaft, whereinthe mesh structure is configured to contact an interior wall of theblood vessel when the mesh structure is in a deployed state, and whereinthe contacts are arranged along the mesh structure.
 20. Theneuromodulation catheter of claim 1, further comprising a balloon at thedistal portion of the shaft, wherein the balloon carries the contactsand is configured to place the contacts into contact with an interiorwall of the blood vessel when expanded.
 21. The neuromodulation catheterof claim 1 wherein: the digital neural signals comprise electroneurogram(ENG) signals, and wherein the digitizer is configured to filter signalsreceived from the contacts to differentiate the ENG signals fromelectromyogram (EMG) signals before transmitting the digital neuralsignals to the read/write module; and the digitizer further comprises atelemetry module configured to wirelessly transmit the digitized signalsfrom within the patient to the read/write module.
 22. Theneuromodulation catheter of claim 1 wherein: the digitizer is at thedistal portion of the elongated shaft proximal to the contacts, whereinthe digitizer chip comprises— a telemetry module configured towirelessly transmit the digitized signals from within the patient to theread/write module; an analog to digital circuit; and a amplifierassembly configured to filter signals received from the contacts todifferentiate the electroneurogram (ENG) signals from electromyogram(EMG) signals before transmitting the digital neural signals to theread/write module; and the contacts are further configured to deliverneuromodulation energy to the nerves along the blood vessel of thepatient and detect the analog neural signals before and/or after thedelivery of the neuromodulation energy.
 23. A neuromodulation catheter,comprising: a shaft configured to be moved through a lumen of a bloodvessel of a human and having a distal portion from which therapeuticenergy is delivered to a target site within the blood vessel; and adigitizer at the distal portion of the shaft and having a plurality ofcontacts, wherein the contacts are configured to detect analog neuralmeasurements from within a blood vessel in a human, and wherein thedigitizer is configured to digitize the analog neural measurements andproduce digital neural signals.
 24. The neuromodulation catheter ofclaim 23 wherein the contacts are configured to deliver the therapeuticenergy to the target site.
 25. The neuromodulation catheter of claim 23wherein the digitizer is one of a plurality of digitizers at the distalportion of the shaft.
 26. The neuromodulation catheter of claim 23wherein the digitizer comprises an analog to digital circuit configuredto digitize the analog neural signals, a memory to store the digitalneural signals, and a telemetry system configured to transmit thedigital neural signals to an extracorporeal receiver located outside ofthe human.
 27. A neuromodulation system, comprising: a neuromodulationcatheter having a distal portion and a proximal portion and configuredto be moved through a lumen of a blood vessel of a human, wherein theneuromodulation catheter comprises— a plurality of contacts configuredto detect analog neural measurements from within the blood vessel of thehuman; and a digitizer operably coupled to the contacts, wherein thedigitizer is configured to digitize the analog neural measurements andproduce digital neural signals; and a read/write module communicativelycoupled to the digitizer and configured to receive the digital signalsof the neural measurements.
 28. The neuromodulation system of claim 27wherein the digitizer and the read/write module are wirelessly coupledto each other.
 29. The neuromodulation system of claim 27 whereincontacts are integrated with the digitizer.
 30. The neuromodulationsystem of claim 27 wherein the distal portion of the neuromodulationcatheter comprises at least one energy delivery element configured todeliver to therapeutically-effective neuromodulation energy to neuralfibers at a target site within the blood vessel of the human.
 31. Theneuromodulation system of claim 30 wherein the contacts define the atleast one energy delivery element such that the contacts are configuredto deliver neuromodulation energy to neural fibers and detect neuralmeasurements before and after delivering the neuromodulation energy. 32.The neuromodulation system of claim 27 wherein the digitizer is at thedistal portion of the neuromodulation catheter proximate to thecontacts.
 33. The neuromodulation system of claim 27 wherein thedigitizer comprises a amplifier assembly configured to filter signalsreceived from the contacts to differentiate the electroneurogram (ENG)signals from electromyogram (EMG) signals before transmitting digitalneural signals to the read/write module.
 34. The neuromodulation systemof claim 27 wherein: the neuromodulation catheter further comprises aplurality of energy delivery elements configured to delivertherapeutically-effective neuromodulation energy to neural fibers at atarget site within the blood vessel of the human; and the digitizer isone of a plurality of digitizers, wherein each digitizer is proximate toa corresponding energy delivery element.
 35. A neuromodulation system,comprising: a neuromodulation catheter having— an elongated shaft havinga distal portion and a proximal portion, wherein at least the distalportion is configured to be moved within a lumen of a blood vessel of ahuman; an array of contacts at the distal portion of the shaft, whereinthe contacts are configured to detect analog neural signals from withinthe blood vessel; and a transmitter operably coupled to the contacts;and a guide catheter configured to extend over the neuromodulationcatheter and deliver at least the distal portion of the shaft to atarget site within the blood vessel, wherein the guide cathetercomprises— a digitizer configured to receive the analog neural signalsfrom the transmitter, digitize the analog neural signals into digitalneural signals, and transmit the digital neural signals to a read/writemodule external to the human.
 36. A method of detecting neural activityfrom within a blood vessel of a human, the method comprising: deliveringa distal portion of a neuromodulation catheter to a target site withinthe blood vessel of the human, wherein the distal portion comprises aplurality of contacts; recording analog neural signals with thecontacts; digitizing recorded analog neural signals via a digitizeroperably coupled to the contacts, wherein the digitizer is integratedwith the neuromodulation catheter; and transmitting the digital neuralsignals to a read/write module external to the human.
 37. The method ofclaim 36 wherein digitizing the recorded analog neural signals isperformed within the human.
 38. The method of claim 36, furthercomprising filtering the recorded analog neural signals with thedigitizer to differentiate electroneurogram (ENG) signals fromelectromyogram (EMG) signals.
 39. The method of claim 36, furthercomprising filtering the recorded analog neural signals with thedigitizer using quasi-tripole (QT), true-tripole (TT), and/oradaptive-tripole (AT) signal processing techniques to detectelectroneurogram (ENG) signals, wherein the analog neural signals arefiltered before digitizing.
 40. The method of claim 36, furthercomprising: delivering neuromodulation energy to a target site withinthe blood vessel of the human via at least one energy delivery element,wherein the recording, digitizing, and transmitting steps are performedbefore and after delivery of the neuromodulation energy; and comparingelectroneurogram (ENG) signals recorded before and after delivery of theneuromodulation energy.
 41. The method of claim 40, further comprisingdelivering neuromodulation energy at the target site for a second timewhen there is not a decrease in the ENG signal detected after energydelivery.
 42. The method of claim 40 wherein the target site is a firsttarget site, and wherein the method further comprises: repositioning theenergy delivery element to a second target site within the blood vessel;and delivering neuromodulation energy to the second target site via theenergy delivery element, wherein the recording, digitizing, andtransmitting steps are performed before and after delivery of theneuromodulation energy.
 43. The method of claim 36 wherein: recordinganalog neural signals further comprises recording a plurality of analogneural signals taken during a plurality of different time intervals;digitizing recorded analog neural signals further comprises digitizingeach of the recorded neural signals; transmitting the digital neuralsignals to the read/write module further comprises transmitting each ofthe digital neural signals to the read/write module after each timeinterval; and averaging the digital neural signals at the read/writemodule to determine nerve activity proximate to the contacts.
 44. Themethod of claim 36, further comprising comparing electroneurogram (ENG)signals taken at different time intervals.
 45. The method of claim 36wherein transmitting the digital neural signals comprises wirelesslytransmitting the digital neural signals from within the human to theread/write module.
 46. The method of claim 36 wherein transmitting thedigital neural signals comprises inductively transmitting the digitalneural signals from within the human to the read/write module.
 47. Themethod of claim 36 wherein the neuromodulation catheter comprises ahandle at the proximal portion of the neuromodulation catheter, andwherein the digitizer is at the handle.
 48. The method of claim 36,further comprising delivering neuromodulation energy via at least oneenergy delivery element to a target site within the blood vessel of thehuman, wherein the recording, digitizing, and transmitting steps areperformed before and/or after delivery of the neuromodulation energy.49. The method of claim 48 wherein delivering the neuromodulation energyvia the energy delivery element comprises delivering the neuromodulationenergy via the plurality of contacts.
 50. The method of claim 48 whereinthe energy delivery element comprises a radiation emitter, and whereindelivering neuromodulation energy via the energy delivery elementcomprises delivering radiation to a vessel wall at the target site. 51.The method of claim 48 wherein the energy delivery element comprises anultrasound transducer, and wherein delivering neuromodulation energy viathe energy delivery element comprises delivering ultrasound waves to avessel wall at the target site.
 52. The method of claim 48 wherein theenergy delivery element comprises a cryotherapeutic applicator, andwherein delivering neuromodulation energy via the energy deliveryelement comprises delivering cryotherapeutic cooling to a vessel wall atthe target site.